Non-Hodgkin Lymphoma

June 1, 2015
Andrew M. Evens, DO, MS

,
Jane N. Winter, MD

,
Leo I. Gordon, MD

,
Brian C. H. Chiu, PhD

,
Richard Tsang, MD

,
Steven T. Rosen, MD

This management guide covers the risk factors, screening, diagnosis, staging, and treatment of non-Hodgkin lymphoma.

Overview

Non-Hodgkin lymphoma (NHL) is the sixth most commonly diagnosed cancer in both men and women in the United States. In 2015, it is estimated that there will be 71,850 new cases of NHL (39,850 men and 32,000 women) and 19,790 deaths from NHL. The disease represents approximately 4.3% of all cancer diagnoses (4.7% in males and 4% in females). Notably, incidence rates of NHL almost doubled between 1970 and 1990 but have stabilized since the late 1990s among general populations. Some of this increase may be artifactual, resulting from improved diagnostic techniques and access to medical care, or directly related to the development of NHL in 25- to 54-year-old men with human immunodeficiency virus (HIV) infection. However, additional factors must be responsible for this unexpected increase in frequency of NHL that has been observed throughout the United States.

The increases have been more pronounced in whites, males, the elderly, and those with NHL diagnosed at extranodal sites. Similar findings have been reported in other developed countries. In the United States, incidence rates increased significantly during 2002-2011 for marginal zone lymphoma (average 1.7% per year), mantle cell lymphoma (MCL) (1.7% per year), adult T-cell leukemia/lymphoma (6.6% per year), and natural killer (NK)/T-cell lymphoma (3.5% per year) but decreased for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (−1.4% per year).

Sidebar: Analysis of pre-diagnosis blood specimens for evidence of t(14;18) in patients with follicular lymphoma revealed that progression to follicular lymphoma may occur up to 20 years later in apparently healthy individuals carrying this marker. Investigators estimated that for individuals with a high frequency of peripheral blood t(14;18), the risk of developing follicular lymphoma may be as high as 23-fold that of controls. This marker of risk was present many years before diagnosis in patients. (Roulland S et al: J Clin Oncol 32:1347-1355, 2014).

Epidemiology

Gender

The overall incidence of lymphoma is higher in men than in women. The age-adjusted incidence rate between 2007 and 2011 was about 45% higher in males (23.9 per 100,000) than in females (16.3 per 100,000). Although the overall NHL incidence rates remained unchanged during 2002-2011 among men and women, rates for marginal zone lymphoma and adult T-cell leukemia/lymphoma (ATLL) increased significantly in men, and to a lesser degree, in women.

Age

The incidence of NHL overall and of most histologic subtypes rises exponentially with increasing age. In persons older than 65, the incidence was 91.6 (112.3 males and 76.9 females) per 100,000 persons in 2007-2011. Except for high-grade lymphoblastic and Burkitt lymphomas (the most common types of NHL seen in children and young adults), the median age at presentation for all subtypes of NHL exceeds 50 years.

Race/Ethnicity

The incidence of NHL varies by race/ethnicity, with non-Hispanic whites (20.6 per 100,000 persons) at higher risk than blacks (14.3 per 100,000), Asian/Pacific Islanders (13.4 per 100,000), and Hispanics (17.7 per 100,000) during 2007-2011. Most histologies, particularly low-grade small lymphocytic and follicular lymphomas, are more common in whites than in blacks. Only peripheral T-cell lymphoma (PTCL), mycosis fungoides, and Sézary syndrome are more common in blacks than in whites.

Geography

NHL is most common in developed countries, with the United States having the highest rate worldwide. The lowest NHL rates are found in eastern and south central Asia (2 to 3 per 100,000 population). Certain endemic geographic factors appear to influence the development of NHL in specific areas. Human T-cell lymphotropic virus-1 (HTLV-1)-associated ATLL occurs more frequently where HTLV-1 is endemic, in southern Japan and the Caribbean, and it occurs sporadically in Brazil, sub-Saharan Africa, the Middle East, and the southeastern United States. The seroprevalence in southwest Japan is 16%, although the lifetime risk of ATLL for these persons is 2% to 6%.

The incidence of Burkitt NHL in Africa (Nigeria and Tanzania) is 6 to 8, compared with 0.4 in the United States. Further, the clinical features of Burkitt lymphoma in Africa differ from those of cases reported to the American Burkitt Lymphoma Registry. Etiologic endemic factors include malaria as a source of chronic B-cell antigenic stimulation and Epstein-Barr virus (EBV)-induced immortalization of B lymphocytes. Heavy-chain disease is a disorder of B-lymphoid cells characterized by diffuse thickening of the small intestine due to a lymphoplasmacytic infiltrate with secretion of incomplete IgA heavy chains. Pathologically, it is a mucosa-associated lymphoid tissue (MALT) lymphoma of the small bowel. This clinicopathologic entity is rarely encountered in individuals other than those of Mediterranean ethnic origin.

Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean, Africa, China, Japan, the Middle East, and Latin America. PTCLs are more common in Europe and China than in North America. They represent about 4% of lymphomas in the United States.

Disease Sites

The NHLs are a heterogeneous group of neoplasms that usually arise or present in lymphoid tissues, such as lymph nodes, spleen, and bone marrow, but they may arise in almost any tissue. The most frequent sites for extranodal lymphomas, which constitute about 20% to 30% of all lymphomas (peripheral T-cell NHL, 70% to 80%; follicular, 8% to 10%), are the stomach, skin, oral cavity and pharynx, small intestine, and central nervous system (CNS). Although primary CNS lymphomas are rare (3% to 4% of CNS), there has been a threefold increase in incidence from the 1960s to the mid-1990s, even if patients with HIV infection and other types of immunosuppression are excluded. However, there has been an overall decline in the incidence of primary CNS lymphomas in the United States since 1995, driven mainly by the changing incidence in young and middle-aged men. The rate has continued to increase in men older than 65 and in women. Each of these sites may be involved singularly (ie, primary extranodal lymphoma) or as secondary extranodal sites concomitantly with other systemic disease.

Survival

The potential curability of NHL varies among the different histologic subtypes and is related in part to stage at presentation. The 5-year relative survival rate of patients with NHL increased from 47% between 1975 and 1977 to approximately 71% between 2004 and 2010. These improvements in survival occurred mainly in patients with intermediate- to high-grade histologies. The natural history (survival rates) for indolent lymphomas was unchanged from the 1950s to the early 1990s; however, recent Surveillance, Epidemiology, and End Results (SEER) and other data have shown improved overall survival rates for patients with follicular lymphoma.

Sidebar: Investigators from the International Lymphoma Epidemiology Consortium (InterLymph)pooled individual-level data from 17,471 NHL patients and 23,096 controls in 20 case-control studies to estimate the associations between 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. In the 11 associated monographs, they identified common risk factors among subtypes as well as risk factors that appeared distinct among individual subtypes, suggesting both subtype-specific and shared underlying mechanisms (Morton LM, et al: J Natl Cancer Inst Monogr. 2014:130-144, 2014).

Etiology, Pathogenesis, and Risk Factors

Chromosomal Translocations and Molecular Rearrangements

Nonrandom chromosomal and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype (Table 1). The most commonly associated chromosomal abnormality in NHL is the t(14;18)(q32;q21) translocation, which is found in 85% to 90% of follicular lymphomas and 25% to 30% of higher-grade B-cell NHLs. This translocation results in the juxtaposition of the BCL2 apoptotic inhibitor “oncogene” at chromosome band 18q21 to the heavy-chain region of the immunoglobulin locus within chromosome band 14q32.

The t(11;14)(q13;q32) translocation results in overexpression of BCL1 (cyclin D1/PRAD 1), a cell-cycle–control gene on chromosome 11q13, and is characteristically associated with MCL. The t(3;16)(q27;p11) translocation makes the gene for the interleukin (IL)-2 receptor a partner of BCL6, which is expressed in diffuse large B-cell lymphoma (DLBCL). Chromosomal translocations involving 8q24 lead to c-myc deregulation, which is seen in nearly all cases of Burkitt lymphoma, including those associated with HIV infection, and a subset of DLBCL.

Next-generation sequencing studies have documented frequent mutations in NHL (many involve alterations in epigenetic regulators), including EZH2, CREBBP, E300, MLL2, MEFB2 mutations in follicular lymphoma; EZH2, MYD88, CREBBP, E300, MLL2, and MEFB2 mutations in DLBCL; NOTCH1, MYD88, XPO1, KLHL6, and SF3B1 mutations in CLL; NOTCH1 mutation in MCL; and TET2, DNMT3A, IDH2, RHOA, FYN, ATM, B2M, and CD58 mutations in PTCLs. In addition, recently presented data further showed the functional importance of EZH2 in lymphomagenesis and its cooperation with BCL6.

Sidebar: The Melnick laboratory published data showing that EZH2 is required for B lymphocytes to form germinal centers and that EZH2 mutations convert EZH2 into a “super-repressor” that permanently locks chromatin into a repressive state that causes lymphomas to arise from normal B lymphocytes. Further, EZH2 had to cooperate with BCL6, which also serves as a gene repressor. The combined and coordinated epigenetic actions of EZH2 and BCL6 appeared to be required for lymphomagenesis (Béguelin W et al: Cancer Cell 23:677-692, 2013).

Environmental Factors

Environmental factors also may play a role in the development of NHL. Chemicals that have been linked to the development of NHL include a variety of pesticides and herbicides (2,4-D-organophosphates, chlorophenols) and solvents and organic chemicals (benzene, carbon tetrachloride, trichloroethylene). There is some evidence that the association between pesticides and NHL risk was limited to t(14;18)-positive NHL cases.

TABLE 1: Correlation of chromosomal abnormalities in NHL with histology, antigen rearrangement, and oncogene expression

Viruses

Several viruses have been implicated in the pathogenesis of NHL, including EBV, HTLV-1, Kaposi sarcoma–associated herpesvirus (KSHV, also known as human herpesvirus 8), and hepatitis C virus (HCV). Meta-analyses have shown a 13% to 15% HCV seroprevalence in certain geographic regions among persons with B-cell NHL, especially marginal zone NHL.

EBV is a DNA virus that has been associated with Burkitt lymphoma (particularly in areas of Africa where the virus is endemic), Hodgkin lymphoma, lymphomas in immunocompromised patients (ie, organ transplant recipients and HIV-infected persons), sinonasal lymphoma (Asia and South America), and sporadically in other B- and T-cell lymphomas. In contrast to studies performed in European patients, Mexican patients with intestinal lymphomas show a high frequency of EBV positivity; this finding is not limited to T-cell NHLs but rather includes a significant portion of B-cell NHLs. EBV can transform lymphocytes perpetually in culture. B lymphocytes from normal EBV-positive subjects have been shown to grow as tumors in mice with severe combined immunodeficiency.

HTLV-1 is a human retrovirus that establishes a latent infection via reverse transcription in activated T-helper cells. A minority (3% to 5%) of carriers develop ATLL. An HTLV-1–like provirus has been detected in some patients with mycosis fungoides, although conflicting findings have been reported. KSHV-like DNA sequences are frequently detected in primary effusion lymphomas, in patients with Kaposi sarcoma, and in those with multicentric (plasma cell variant) Castleman disease. HCV infection is associated with the development of clonal B-cell expansions and certain subtypes of NHL, particularly in the setting of essential (type II) mixed cryoglobulinemia. HCV may predispose B cells to malignant transformation by enhancing signal transduction on binding to the CD81 (TAPA-1) molecule.

Sidebar: An international consortium examined the prognostic impact of EBV in more than 700 patients with DLBCL treated with R-CHOP. There were no significant survival differences observed in EBV-positive DLBCL versus EBV-negative DLBCL; however, patients with EBV and CD30 coexpression had inferior survival. Coexpression of EBV-encoded RNA and CD30 was characterized by increased nuclear factor (NF)-κB activity, cell proliferation, and cell-cycle progression (Ok CY et al: Clin Cancer Res 20:2338-2349, 2014).

Bacterial Infections

Infection with Borrelia burgdorferi, the causative agent in Lyme disease, has been detected in about 35% of patients with peripheral cutaneous B-cell lymphoma in Scotland. A near-complete clinical and histologic remission of a primary marginal zone B-cell lymphoma was observed after eradication of B burgdorferi with antibiotic treatment. Gastric MALT lymphoma is seen most frequently, but not exclusively, in association with Helicobacter pylori infection. Studies indicate that Campylobacter jejuni and immunoproliferative small intestinal disease (α-heavy chain disease) are related. Some reports noted an association between infection with Chlamydophila psittaci and ocular adnexal lymphoma. The infection was found to be highly specific and does not reflect a subclinical infection widespread among the general population. Responses to antibiotics have been reported. Attempts to confirm this association in the Western Hemisphere, however, have been unsuccessful.

Immune Modulation

Congenital and acquired states of immunosuppression that are associated with increased risk include ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, X-linked lymphoproliferative syndrome, and severe combined immunodeficiency.

Acquired immunodeficiency states, such as HIV infection, are associated with relative increased risk of NHL of 75 to 100 compared with the general population, although recent data in the post-HAART (highly active antiretroviral therapy) era suggest it has decreased. These NHLs are usually high-grade and often present with extranodal disease. Furthermore, iatrogenic immunosuppression (eg, solid organ transplant [SOT] or hematopoietic stem cell transplant [SCT] recipients) have a significantly increased risk of NHL. The absolute risk of NHL after SOT is 1% to 3% after kidney transplant vs more than 10% after intestinal, cardiac, or multi-organ transplants; patients who have had the latter warrant higher-dose immunosuppressive therapy.

An increased incidence of gastrointestinal (GI) lymphomas is seen in patients with celiac (nontropical) sprue and inflammatory bowel disease, particularly Crohn disease. An aberrant clonal intraepithelial T-cell population can be found in up to 75% of patients with refractory celiac sprue before the development of overt T-cell lymphoma using immunophenotyping and T-cell receptor gamma gene rearrangement polymerase chain reaction (PCR) techniques. Systemic lupus erythematosus and rheumatoid arthritis have been associated with B-cell lymphoma. Sjögren syndrome has been associated with NHL overall, DLBCL, and marginal zone lymphoma.

Patients who receive chemotherapy and/or radiation therapy are also at increased risk for developing subsequent secondary NHL. Meta-analysis of cohort studies showed that blood transfusion was associated with a 20% increase in the risk of NHL. The association was similar for men and women as well as for transfusion given before or after 1992. In contrast, case-control studies in general reported no association.

Lifestyle Factors

Several studies have reported an excess risk of NHL in association with diets high in fat and meat products. Some studies have suggested that ultraviolet radiation exposure and alcohol intake may be linked inversely with NHL risk.

Genetic Susceptibility

Several reports have implicated a role for genetic variants in the risk of NHL, including genes that influence DNA integrity and methylation; genes that alter B-cell survival and growth; and genes that involve immune function/inflammation, oxidative stress, and xenobiotic metabolism. Recent genome-wide association studies (GWAS) conducted by investigators in the International Lymphoma Epidemiology Consortium (InterLymph) have identified a number of predisposing single nucleotide polymorphisms (SNPs) for NHL, including 11q23.3 (CXCR5), 11q24.3 (ETS1), 3q28 (LPP), 18q21.33 (BCL2), and 8q24.21 (PVT1) linking variants outside the HLA region to follicular lymphom risk; 6p25.3 (EXOC2), 6p21.33 (HLA-B), 2p23.3 (NCOA1), and 8q24.21 (PVT1) supporting the role of immune recognition and immune function in the pathogenesis of DLBCL; rs9461741 (BTNL2) and rs2922994 (HLA-B) suggesting that genetic variation in the HLA region influences susceptibility to marginal zone lymphoma; and 10q23.31 (ACTA2/FAS), 18q21.33 (BCL2), 11p15.5 (C11/F21), 4q25 (LEF1), 2q33.1 (CASP10/CASP8), 9p21.3 (CDKN2B-AS1), 18q21.32 (PMAIP1), 15q15.1 (BMF), and 2p22.2 (QPCT) pointing to genes involved in apoptosis and CLL risk.

Sidebar: Investigators in the InterLymph conducted a comprehensive multi-stage GWAS on 5,216 patients with DLBCL and 12,223 controls. The authors identified five independent SNPs in four loci that achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2); rs2523607 at 6p21.33 (HLA-B); rs79489871 at 2p23.3 (NCOA1); and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1). These data provide substantial new evidence for genetic susceptibility to DLBCL and suggest pathways involved in immune recognition and immune function in the pathogenesis of this B-cell malignancy (Cerhan JR et al: Nat Genet 46:1233-1238, 2014).

Signs and Symptoms

Fever, weight loss, and night sweats, referred to as systemic B symptoms, as well as fatigue and weakness, are more common in advanced or aggressive NHL, but may be present in all stages and histologic subtypes.

Low-Grade Lymphomas

Painless, slowly progressive peripheral adenopathy is the most common clinical presentation in patients with low-grade lymphomas. Patients sometimes report a history of waxing and waning adenopathy before seeking medical attention. Spontaneous regression of enlarged lymph nodes can occur and can cause a low-grade lymphoma to be confused with an infectious condition.

Primary extranodal involvement and B symptoms are uncommon at presentation; however, both are more common in advanced or end-stage disease. Bone marrow is frequently involved, sometimes in association with cytopenias. Splenomegaly is seen in about 40% of patients, but the spleen is rarely the only involved site at presentation (eg, splenic marginal zone lymphoma).

Aggressive-Histology Lymphomas

The clinical presentation of aggressive-histology lymphomas is more varied. Although the majority of patients present with adenopathy, more than one-third present with extranodal involvement, the most common sites being the GI tract (including Waldeyer ring), skin, bone marrow, sinuses, bone, and CNS. B symptoms are more common, occurring in about 30% to 40% of patients. Lymphoblastic lymphoma often typically presents with an anterior superior mediastinal mass with possible superior vena cava (SVC) syndrome, and leptomeningeal disease with possible cranial nerve palsies. American patients with Burkitt lymphoma often present with a large abdominal mass and symptoms of bowel obstruction.

Screening and Diagnosis

No effective methods are available for screening or identifying populations at high risk for developing NHL. A definitive diagnosis can be made only by biopsy of pathologic lymph nodes or tumor tissue. It is critical to perform an excisional lymph node biopsy (fine-needle aspiration [FNA] is insufficient for diagnostic purposes) to avoid false-negative results and inaccurate histologic classification. One study showed that when FNAs and biopsy results for the diagnosis of NHL and Hodgkin lymphoma were compared, only 12% of FNAs correlated with subsequent excisional biopsy results. When clinical circumstances make surgical biopsy of involved lymph nodes or extranodal sites prohibitive, a core biopsy obtained under computed tomographic (CT) or ultrasonographic guidance may suffice, but this requires the integration of immunophenotypic analysis (immunohistochemistry [IHC] and/or flow cytometry) and often genotypic analysis (cytogenetics and/or molecular studies, such as fluorescent in situ hybridization [FISH] and PCR) for accurate diagnosis. A formal review by an expert hematopathologist is mandatory.

Initial Diagnostic Evaluation

Initial diagnostic evaluation for lymphoproliferative malignancy should include the following:

• Careful history (night sweats, weight loss, fever; neurologic, musculoskeletal, or GI symptoms).

• Physical examination (lymph nodes, including submental, infraclavicular, epitrochlear, iliac, femoral, and popliteal nodes; pericardial rub, pleural effusion, distended neck and/or upper extremity veins in SVC syndrome; breast masses; hepatosplenomegaly, bowel obstruction, renal mass, and testicular or ovarian mass; focal neurologic signs, such as plexopathy, spinal cord compression, nerve root infiltration, and meningeal involvement; skin lesions).

• Biopsy of peripheral lymphadenopathy (excisional biopsy recommended).

• CT scan of the neck (cervical lymph nodes, Waldeyer ring) and chest (mediastinal, hilar, or parenchymal pulmonary disease).

• CT scan of the abdomen and pelvis (enlarged lymph nodes, splenomegaly, filling defects in the liver and spleen).

• Bone marrow biopsy and aspirate.

• FDG-PET (fluorodeoxyglucose positron emission tomography) scans (select cases: aggressive NHL histologies) for staging at diagnosis, response, assessment, and relapse; off of a clinical trial, “early” repeated PET scans (eg, following two cycles) are not advocated, in part because of the frequent disparate interpretation of PET scans as well as lack of predictability of impact of modification of treatment.

Sidebar: An imaging working group composed of representatives from major international cooperative groups published revised guidelines on imaging for staging and response assessment of lymphoma. This included re-assessment of use (and methods) of FDG-PET/CT scanning, re-appraisal of bone marrow biospy, and post-remission surveillance scanning (Barrington SF et al: J Clin Oncol 32:3048-3058, 2014).

• Complete blood cell count with differential and platelet count (peripheral blood lymphocytosis with circulating malignant cells is common in low-grade lymphoma and MCL). Bone marrow and peripheral blood involvement may be present, and the distinction between leukemia and lymphoma is difficult to make in some cases.

TABLE 2: Immunophenotypic and histochemical markers of B-cell lymphomas/leukemias

• General chemistry panel (including lactate dehydrogenase [LDH] level determination) is mandatory.

• Hepatitis B virus (HBV) and HCV panels should be considered, especially in patients anticipated to receive monoclonal antibody therapy and/or chemotherapy (HBV: at least HBV surface antigen and HBV core antibody; HCV: HCV antibody).

• HIV serology in at-risk patients with DLBCL and other aggressive and Burkitt histologies; HTLV-1 serology in select patients with cutaneous T-cell lymphoma (CTCL), especially if they have hypercalcemia.

• Cytogenetic and molecular analyses of lymph node, bone marrow, and peripheral blood (select cases).

• Immunophenotyping can be of particular benefit in distinguishing B-cell CLL/SLL from other lymphomas (Table 2). Immunophenotyping and histochemical markers may also be of benefit in distinguishing T-cell lymphomas/leukemias (Table 3).

TABLE 3: Immunophenotypic and histochemical markers of T-cell lymphomas/leukemias

• Examination of cerebrospinal fluid and consideration of intrathecal chemotherapy prophylaxis in patients with (1) diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, breast, or multiple extranodal sites; (2) high-grade lymphoblastic lymphoma and Burkitt lymphoma and its variants; (3) primary CNS lymphoma if no evidence of increased intracranial pressure.

• Upper GI endoscopy in patients with head and neck involvement (tonsil, base of tongue, nasopharynx) and those with a GI primary NHL; MCL is associated with a high incidence of occult GI involvement.

• Ultrasonography of opposite testis in patients with a testicular primary.

• Spinal magnetic resonance imaging (MRI) scan for epidural disease when clinically indicated (critical in the evaluation of suspected spinal cord involvement).

Pathology

The Working Formulation was proposed in 1982 as a modification of the Rappaport classification of NHL based on morphology and biologic aggressiveness. Although many subtypes were not recognized, including T-cell lineage lymphomas, a revised European-American classification of lymphoid neoplasms (REAL classification) was introduced in 1994 incorporating T-cell malignancies, subtypes of Hodgkin lymphoma, and newer defined lymphoma-proliferative disorders. The World Health Organization (WHO) classification for lymphomas (introduced in 1999 and updated in 2008) uses the principles of the REAL classification, defining each entity according to morphologic features, immunophenotype, genetic features, postulated normal counterpart, and clinical features.

WHO Classification

The modifications in the 2008 WHO classification included incorporation of further site-specific lymphoma subtypes, recognition of age as a defining feature of some diseases, and inclusion of several borderline and provisional categories (Table 4). The most frequently occurring clinical entities recognized within the WHO classification are DLBCL (31%), follicular lymphoma (22%), marginal zone/MALT lymphoma (8%), SLL (7%), and MCL (6%), whereas all noncutaneous T-cell lymphomas represent approximately 10% of NHL diagnoses in the United States.

TABLE 4: WHO classification of the mature B-cell, T-cell, and NK-cell neoplasms (2008)

The WHO classification includes three types of follicular lymphoma (grades 1/2, 3a, and 3b). Grading of follicular lymphoma is based in part on the number of centroblasts or large cells per high-power field. Notably, the presence of any diffuse areas (ie, non-follicular pattern) with large B cells should be designated as DLBCL. Further, some cases may include a composite of different histologic subtypes within the same lymph node excision (eg, follicular lymphoma and DLBCL). Grade 3b follicular lymphoma indicates sheets of large cells within a follicle (ie, maintained follicular architecture). Grade 3b follicular lymphoma more closely resembles DLBCL at the molecular level.

In the revised WHO classification, further clinicopathologic subtypes were added, namely DLBCL associated with inflammation and EBV and DLBCL in the elderly. In terms of T-cell lymphomas, anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive, is considered a distinct disease, which is distinguished from the provisional entity of ALCL, ALK-negative. Three new variants of primary cutaneous T-cell lymphoma were also introduced (Table 4). In addition, an indolent T-cell lymphoproliferative disease of the GI tract has been described .

Staging and Prognosis

Determining the extent of disease in patients with NHL provides prognostic information and is useful in treatment planning. However, histologic subclassification (WHO classification) is the primary determinant of survival and potential for cure. Compared with patients with limited disease, those with extensive disease usually require different therapy, and certain extranodal sites of involvement, such as the CNS and testes, require specific treatment modalities.

Ann Arbor System

Although initially devised for Hodgkin lymphoma, the Ann Arbor system has been routinely applied to NHL (Table 5). Because Hodgkin lymphoma commonly spreads via contiguous lymph node groups, this system is based primarily on the distribution of lymphatic involvement with respect to the diaphragm and the presence of extralymphatic organ involvement. The Ann Arbor system does not reflect the noncontiguous nature of disease spread in NHL, does not discriminate well between stages III and IV disease, and fails to account for tumor bulk or number of extranodal sites.

Some trials in Burkitt and Burkitt-like lymphoma use the St. Jude/Murphy staging system, in part to more completely describe the extent of extranodal disease. Unlike the current WHO classification, this staging system recognizes Burkitt leukemia as a separate entity. Moreover, this system was developed when surgery was used for diagnostic and therapeutic purposes. Patients are also typically stratified into two risk groups, with low-risk patients defined as having a normal LDH level and a single focus of disease measuring less than 10 cm and all others considered to be high-risk.

TABLE 5: Ann Arbor staging classification for NHL

Prognostic Factors

Histology (by WHO classification) remains the major determinant of treatment outcome and prognosis. Newer pathologic technologic methods, such as gene expression profiling, have emerged as important determinants of outcome. However, these currently remain research-based; routine clinical factors continue to be prognostically important in indolent and aggressive NHLs.

The International Prognostic Index

The International Prognostic Index (IPI) was developed in the pre-rituximab (R) era.

TABLE 6: NCCN–International Prognostic Index

It has served as a useful guide for prognosis in patients with aggressive DLBCL treated with cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisone (CHOP)-like therapy. Because younger patients are more likely to be considered for more intensive investigational regimens, an age-adjusted model for patients 60 years and younger was developed that required only three clinical factors-stage (III or IV), high LDH level, and performance status-to predict survival. Notably, the IPI has remained a valid prognostic index in the rituximab era, but it has lost much of its capacity to discriminate between risk groups in the setting of R-CHOP chemotherapy. On the basis of raw data from the National Comprehensive Cancer Network (NCCN) lymphoma database, a new prognostic model was built based solely on clinical factors (Table 6). The NCCN-IPI identifies low- and high-risk cohorts with 5-year overall survivals of 96% and 33%, respectively; is easy to use; and is more powerful than its predecessor, the IPI.

A prognostic factor model was devised based on 919 cases of follicular lymphoma, known as the Follicular Lymphoma IPI (FLIPI; Table). Multivariate analysis showed that age, Ann Arbor stage, number of nodal sites, LDH level, and hemoglobin level were predictors of overall survival. An analysis of the FLIPI in the post-rituximab era has been reported (FLIPI-2). Multivariate analysis showed that elevated beta2-microglobulin level, longest nodal diameter over 6 cm, bone marrow involvement, anemia, and age over 60 years independently predicted survival. Including all patients (N = 832) with 0, 1 or 2, or 3 to 5 factors, the 3-year progression-free survival was 91%, 69%, and 51%, respectively (P = .00001), whereas the 5-year progression-free survival was 79%, 51%, and 20%, respectively (P = .00001). Among patients treated with rituximab-containing regimens only (n = 559), the FLIPI-2 remained predictive of outcome (3-year progression-free survival of 89%, 73%, and 57%, respectively; P = .001).

The MCL International Prognostic Index (MIPI) was created from 455 advanced-stage MCL patients treated within three German clinical trials. It consisted of several clinical factors. The simplified MIPI (sMIPI) is the sum of increasing points for grouped values of age, performance status, LDH level greater than the upper limit of normal, and leukocyte count and is scored as low-risk (0-3 points), intermediate-risk (4-5 points), and high-risk (> 5 points; Table 8). Patients with low or intermediate risk according to the sMIPI had a 5-year overall survival of more than 75% to 80% compared with 38% for patients with high risk (> 5 factors).

Immunobiologic Factors

Various immunobiologic factors have been suggested as predictors of outcome in NHL.

TABLE 7: Follicular lymphoma International Prognostic Indices

Immunophenotype

A number of studies have suggested that patients with aggressive T-cell NHL have a higher relapse rate and decreased overall survival compared with patients who have B-cell disease, especially in the post–rituximab era. The Lunenberg Biomarker Consortium has shown that Ki-67 greater than 75% and CD5 expression greater than 75% predict inferior survival, and the integration of these two markers in addition to high BCL2 expression improved the prognostication of the IPI. Studies using the Ki-67 antibody, a marker of nuclear proliferation, have shown that increased tumor cell proliferation is a poor prognostic factor in MCL.

Cytogenetic abnormalities and oncogene expression

Mutations of p53 are associated with histologic transformation in follicular NHL, which is a phenomenon frequently associated with a poor prognosis. Expression of BCL2 in DLBCL has also been associated with inferior survival, whereas BCL6 expression is a marker of germinal center derivation, a predictor of a favorable outcome with CHOP-like therapy. Expression of MYC in DLBCL as a sole abnormality has been shown to portend an inferior prognosis, while concurrent molecular expression of BCL2, MYC, and/or BCL6 in B-cell lymphomas (the so-called double-hit or triple-hit lymphomas) is a particularly poor prognostic sign. The MYD88 L265P somatic mutation has been shown to occur frequently in Waldenströms macroglobulinemia.

TABLE 8: Simplified MCL International Prognostic Index

Molecular Profiling

DNA microarray technology for gene expression profiling (GEP) has identified distinct prognostic subgroups in DLBCL and follicular NHL. Studies in DLBCL have characterized patients into the following subgroups: germinal center B-like DLBCL, activated B-like DLBCL, and a heterogeneous subgroup termed “type-3 DLBCL.” In the pre–rituximab era, patients with germinal center B-like DLBCL had a significantly improved overall survival compared with patients who had the other molecular profiles. In the post-rituximab era, this prognostic difference is less, but still apparent. Studies in follicular NHL identified two gene expression signatures that predicted survival: immune-response 1 and immune-response 2. Interestingly, the genes that defined the prognostic signatures, however, were not expressed in the tumor cells but were expressed by the nonmalignant tumor microenvironment (primarily T cells, macrophages, and dendritic cells). A variety of immunologically active cell types, including specific T-cell subsets and tumor-associated macrophages, have been associated with prognosis in some studies.

Similar data are available in DLBCL regarding gene-expressing studies of the surrounding (nonmalignant) microenvironment. Lenz et al showed that the stromal-1 signature (composed of extracellular-matrix deposition and histolytic infiltration) was associated with a significantly improved outcome compared with stromal-2 (tumor blood-vessel density) in CHOP- and R-CHOP–treated populations. GEP is now able to be performed on formalin-fixed paraffin-embedded tissue, and data continue to be generated linking unique molecular signatures with patient outcome.

Treatment

The therapeutic approach for NHL differs for each subtype. Chemotherapy remains the most important modality (Tables 9 and 10). However, in select instances, radiation therapy or, rarely, surgical resection plays a critical role. Biologic approaches, including monoclonal antibodies (Table 11) and recombinant conjugates, have shown significant clinical activity and are now incorporated into treatment paradigms. In addition, several novel therapeutics targeted against various oncogenic and signaling pathways have been approved, and they continue to be evaluated as a component of front-line treatment (Table 12). Autologous and allogeneic SCTs, traditionally reserved for recurrent or refractory disease, are being evaluated as part of initial therapy in high-risk settings. This section will be organized by NHL subtype to best illustrate the biologic characteristics and therapeutic considerations that determine the management strategy for individual patients. Common NHLs will be covered in depth, whereas less frequent entities will be described in limited detail.

Follicular Lymphoma

Follicular lymphoma accounts for 22% of all NHLs; only DLBCL is more common. The clinical presentation may be nodal or extranodal, and bone marrow involvement occurs in the majority of cases. Extensive intra-abdominal adenopathy without peripheral node enlargement is not uncommon. Clinical behavior is variable, reflecting the heterogeneity of the underlying biology; some patients survive decades, whereas others progress rapidly to resistant disease or transform to a more aggressive histology. There are rare spontaneous remissions. Transformation is common, occurring in 2% to 5% of patients each year and ultimately 30% to 40% of all patients. A recent report suggests that the risk may be lower than previously reported, plateauing after 5 years.

Although follicular lymphoma is generally responsive to treatment, the clinical course is characterized by repeated relapses. Even though there was no improvement in survival for patients with follicular lymphoma for many years, there is now evidence that outcomes are improving. Median survival has reached more than 18 years in some series. It is likely that this is at least in part attributable to use of rituximab in combination with chemotherapy, but survival was already improving before the approval of rituximab.

It is crucial to distinguish between reactive follicular hyperplasia and follicular lymphoma, because the former is a benign condition. Morphologic features as well as the absence of BCL2 staining within the follicle and the absence of CD10 and/or BCL6 protein expression in the interfollicular areas help distinguish reactive follicular hyperplasia from follicular lymphoma. Follicular lymphoma is graded according to the number of admixed centroblasts within the neoplastic follicles. Grade 3 follicular lymphoma, previously known as follicular large cell lymphoma, is now subdivided into two subtypes: Grade 3a is characterized by a mixture of centrocytes and centroblasts within the follicle, whereas grade 3b has only sheets of centroblasts with no residual centrocytes.

The neoplastic lymphocytes in follicular lymphoma express the pan-B markers CD19, CD20, CD22, and CD79a and antigens of the germinal center (including CD10 and BCL6). Most follicular lymphomas express BCL2 protein, which is highly correlated with the t(14;18)(q32;q21). This translocation results in the juxtaposition of the BCL2 oncogene into the immunoglobulin H heavy-chain locus on chromosome 14, resulting in its constitutive expression. Follicular lymphoma grade 3b with BCL6 rearrangement but no t(14;18)(q32;21) may be more closely related to DLBCL than to other follicular lymphomas and is treated as such.

As previously mentioned, the FLIPI is a prognostic index designed specifically for follicular lymphomas based on five adverse prognostic factors (Table 7). Age is the most important factor. Three risk categories have been defined, each consisting of approximately one-third of patients. More than two-thirds of low-risk patients but only one-third of high-risk patients survive 10 years. A modern prognostic scoring system, the FLIPI2, is based on prospectively collected data from the rituximab era (Table 7) and has progression-free survival rather than overall survival as its principal endpoint. Among patients receiving rituximab-containing therapy, it is a robust predictor of clinical outcome. Whereas clinical parameters are surrogates for biologic characteristics, biologic correlates may soon supersede clinical prognostic indicators.

As noted before, investigators from the National Cancer Institute (NCI) previously described gene-expression signatures representing immunomodulatory genes in the microenvironment with prognostic significance. Others have reported that the number of tumor-associated macrophages, specific T-cell subsets, and serum cytokine and chemokine levels are independent predictors of overall survival in follicular lymphoma, underscoring the importance of host response in determining clinical outcome. Consistent with these findings, promising new agents targeting regulators of the T-cell–dependent anti-tumoral effect are now under investigation.

Sidebar: The presence of BCL2 coding sequence mutations has been identified recently as a powerful indicator of poor prognosis, independent of the FLIPI. BCL2 coding sequence mutations correlated with an increased risk of transformation (hazard ratio [HR] = 3.6; 95% confidence interval [CI], 2.0–6.2; P< .001) and risk of lymphoma-related death (median survival: 20.4 years versus 9.5 years; P=.012) and may serve as a supplement to the FLIPI, enhancing its capacity to predict outcome (Correia C et al: Blood 125:658-667, 2015).

Sidebar: Investigators from the MD Anderson Cancer Center reported results of a phase II trial with the humanized anti-PD1 monoclonal antibody, pidilizumab, in combination with rituximab for patients with relapsed follicular lymphoma. Among 32 patients and with 15-month median follow-up, 66% of patients achieved a response, with 52% of responses being complete. Therapy was overall well tolerated, with the most common adverse event being grade 2 respiratory infection in 16% of patients (Westin JR et al: Lancet Oncol 15:69-77, 2014).

TABLE 9: Chemotherapeutic regimens for NHL

TABLE 10: Commonly used salvage regimens for NHL

TABLE 11: Examples of monoclonal antibodies for lymphoid malignancies

Treatment of early-stage disease

For patients with stage I or II follicular lymphoma, radiotherapy continues to be the recommended approach because of the potential for long-term disease-free survival and possible cure. Results from the Princess Margaret Hospital’s series of involved-field radiotherapy (IFRT) for early-stage disease show cumulative relapse rates of 54% and 56% at 15 and 25 years, respectively, with only a 2% risk of relapse beyond 15 years. Analysis of the SEER database for adults with stage I or II follicular lymphoma diagnosed between 1973 and 2004 showed improved disease-specific survival and overall survival with upfront IFRT, compared with all other approaches.

Irradiation alone for clinical stages I and IIA low-grade follicular lymphoma was, in the past, directed to the entire involved lymphoid region, as defined by Kaplan and coworkers, or the involved region plus one additional uninvolved region on each side of the involved nodes. However, targeting just the involved lymph nodes with a margin up to 5 cm, compared with routinely covering the entire lymph node region has been shown by a Canadian study to give equally good results and may reduce long-term risks. Current guidelines for radiation planning utilize target definition with CT simulation and is termed involved-site radiotherapy (ISRT). It is important to note that radiation to large intra-abdominal or pelvic fields may be associated with increased morbidity and thus must be judiciously considered. Conformal or intensity-modulated radiation therapy (IMRT) may be required to spare sensitive organs such as the kidneys and liver. The recommended dose is approximately 30 Gy for nonbulky disease showing prompt regression and 36 Gy for bulky or slowly regressive disease, in 1.75 to 2 Gy daily fractions. A trial from the United Kingdom showed equivalent results comparing 24 Gy with 40 Gy. Because the majority of subsequent relapses occur outside previous radiation fields, often in adjacent or distal lymph nodes, extended-field or total lymphoid irradiation has been used to try to improve cure rates. Clinical series have shown improvement in freedom from relapse only, with no significant difference in long-term survival.

Despite the excellent outcomes associated with radiotherapy, the National Lymphocare Study revealed that the majority of patients in the United States either are observed or are treated with rituximab alone or in combination with chemotherapy, foregoing the potential for cure, even in young patients. Use of functional imaging with PET may improve the results of IFRT by more accurately identifying patients with truly localized disease. Combined-modality therapy has also resulted in excellent disease control, but there is no evidence that this approach improves outcomes compared with radiotherapy alone.

Treatment of advanced-stage disease

The asymptomatic patient. The standard management of asymptomatic patients with follicular lymphoma has been a “watch-and-wait” approach. Treatment is delayed until symptoms or cytopenias intervene or there is impending compromise of vital organs. In the pre-rituximab era, multiple phase III randomized trials comparing immediate chemotherapy with observation for asymptomatic patients with advanced-stage follicular lymphoma showed no difference in outcomes. A phase III trial comparing the watch-and-wait approach with rituximab therapy for asymptomatic low–tumor burden advanced-stage disease has been completed in Europe. Although the median time to new therapy had not been reached at 4 years, there was no survival benefit to initiating therapy with rituximab in asymptomatic patients compared with the watch-and-wait strategy. Although an increasing number of asymptomatic patients with low-burden disease and their physicians are opting to start treatment with rituximab before they are symptomatic or meet standard criteria for therapy, the watch-and-wait strategy continues to be the recommended approach.

An American intergroup trial (E4402) compared two different rituximab dosing regimens in asymptomatic patients with low–tumor burden indolent lymphoma. All patients received rituximab 375 mg/m2 weekly for 4 weeks and responders were randomized to either maintenance rituximab (one dose every 3 months until progression) or re-treatment with four weekly doses of rituximab at the time of progression. Each strategy was continued indefinitely until treatment failure. There was no difference between the two strategies in time to treatment failure. Although time to cytotoxic therapy was slightly longer in patients receiving maintenance rituximab, this came at a cost of four times more rituximab and without an improvement in quality of life. The authors concluded that rituximab re-treatment was the preferred strategy over ongoing maintenance rituximab, if patients and their physicians elect rituximab monotherapy for low–turmor burden follicular lymphoma.

TABLE 12: Examples of targeted treatment agents (non-antibody) for the treatment of lymphoid malignancies

Rituximab. For patients with symptoms or other reasons for treatment, there are many treatment options, including single- or multi-agent chemotherapy, monoclonal antibodies or radioimmunoconjugates, combinations of chemotherapy and immunotherapy with anti-idiotype vaccines, and newer agents such as bortezomib (Velcade) and bendamustine (Treanda). There are few data on the treatment of high–tumor burden disease with single-agent rituximab. Among patients with low-burden disease, overall response rates have ranged from 47% to 74%.

In relapsed or refractory indolent lymphomas, treatment with rituximab results in overall response rates of nearly 50%, with a median response duration of approximately 1 year. To improve on response rates and duration of response, additional doses of rituximab have been administered as “maintenance therapy.” The median event-free survival is prolonged with this approach, especially for previously untreated patients. With a median follow-up of more than 9 years, an early trial of single-agent rituximab has shown that among untreated patients who responded to rituximab, 45% of those who received an additional four doses of rituximab were without progression or other events at 8 years. In previously treated patients, the total duration of benefit from rituximab appears to be the same whether patients receive maintenance rituximab on a scheduled basis or reinduction with rituximab only at the time of disease progression. A confirmatory trial (ECOG 4402, described above) in asymptomatic untreated patients with a low tumor burden has not shown an overall advantage to the maintenance strategy. Maintenance regimens have varied, and the impact of the frequency of administration on the duration of response is unknown.

Rituximab maintenance also impacts progression-free survival among patients treated with chemotherapy alone and those receiving rituximab plus chemotherapy. Among previously untreated patients with follicular lymphoma who responded to immunochemotherapy (R-CVP [rituximab, cyclophosphamide, vincristine, prednisone], R-CHOP, or R-FCM [rituximab, fludarabine, cyclophosphamide, mitoxantrone]), rituximab maintenance resulted in a significant improvement in progression-free survival over observation in the PRIMA phase III trial (6-year; 59% vs 43%; P < .0001), recently updated by Salles and colleagues. Of note, no differences in the response to second-line therapy were noted. The most common grade 3/4 adverse event was infection (39% for rituximab maintenance vs 24% for observation). Among relapsed/refractory patients treated with CHOP or R-CHOP maintenance, rituximab also improved progression-free survival. Whether these results will translate into an overall survival benefit remains to be seen. Questions also remain regarding the impact of maintenance rituximab on the quality of life and the cost of care. Compared with observation, maintenance rituximab has been associated with an increased risk of infectious complications.

Chemotherapy with and without rituximab. For patients with high–tumor burden disease and/or symptoms, the addition of rituximab to chemotherapy has resulted in major improvements in clinical outcome, including overall survival. Four phase III trials comparing combinations of chemotherapy and rituximab with chemotherapy alone in previously untreated patients have all shown benefit for the combination, establishing chemoimmunotherapy as the standard of care for symptomatic patients or those with high–tumor burden disease. Overall response rates and either median time to treatment failure or event-free survival were superior in the chemoimmunotherapy arm in every series. An overall survival benefit has been demonstrated in three of the four trials and in the high-risk subset of the fourth study.

The combination of bendamustine (Treanda) and rituximab was compared with R-CHOP as first-line therapy in previously untreated patients with follicular, indolent, and mantle cell lymphomas, resulting in significantly longer median progression-free survival (69.5 months vs 31.2 months; HR = 0.58). Bendamustine plus rituximab was less myelosuppressive than R-CHOP and resulted in fewer infections, less peripheral neuropathy, and fewer episodes of stomatitis. This combination has become the backbone for the new US intergroup trial in which rituximab-bortexomib-bendamustine is compared with rituximab-bendamustine. The importance of minimal residual disease in follicular lymphoma is not known. There have been recent studies analyzing minimal residual disease, and other prospective trials are ongoing.

Radioimmunotherapy. The anti-CD20 radioimmunoconjugates Y-90 ibritumomab (Zevalin) and I-131 tositumomab (Bexxar) both deliver ionizing radiation to target cells and their neighbors and have proved to be relatively easy to administer, safe, and effective. Response rates are higher and remissions more durable when radioimmunoconjugates are used early in the clinical course. Both agents are likely to have their greatest impact when used earlier in the disease course.

In previously treated patients, Y-90 ibritumomab, a high-energy beta-emitter, yielded an overall response rate of 80% for relapsed or refractory follicular or transformed CD20+ B-cell NHL, with a median duration of response of 14 months. For patients whose disease is refractory to rituximab, response rates with Y-90 ibritumomab are high (74% overall response rate), but the median duration of response is relatively short (6.4 months; range, 0.5 months to 25+ months). The dose-limiting feature of this approach is hematologic toxicity. Short-lived myelosuppression occurs 7 to 9 weeks posttreatment. Dosing is based on weight (0.4 mCi/kg), with a reduction (0.3 mCi/kg) for those with mild thrombocytopenia (platelet count < 100,000/µL). When used to consolidate first partial or complete remission, Y-90 ibritumomab prolonged progression-free survival from 1.1 to 4.1 years. However, only 14% of the 414 patients enrolled on this randomized phase III trial received a rituximab-containing regimen for induction. Now that the addition of rituximab to chemotherapy has become standard of care based on demonstrated improvement in progression-free and overall survival rates, the benefit of consolidation with radioimmunotherapy will need to be evaluated in large numbers of patients treated first with chemoimmunotherapy.

I-131 tositumomab is both a gamma- and a beta-emitter and is individually dosed on the basis of dosimetry to deliver 75 cGy of total-body irradiation. Similar to Y-90 ibritumomab, it is effective in both heavily pretreated relapsed and refractory patients. Heavily pretreated patients with refractory low-grade or transformed NHL had an overall response rate of 65% (20% complete response rate), with a median duration of response of 6.5 months. These rates were notable in view of a response rate of only 28% in the preceding chemotherapy regimen. Like Y-90 ibritumomab, I-131 tositumomab is associated with predictable myelosuppression. Secondary myelodysplasia and leukemia have occurred in patients treated with radioimmunotherapy, but only in patients previously treated with chemotherapy and thereby already at risk. In previously untreated patients, the complete response rate was 75%, with a 5-year progression-free survival of 59%. These data must be interpreted carefully, because this study enrolled a relatively young patient population (median age, 49 years) with low-bulk disease, a group that some physicians would choose to observe rather than treat.

The American intergroup completed a phase III trial comparing CHOP followed by I-131 tositumomab with R-CHOP in treatment-naive patients. Outcomes were excellent with either strategy. R-CHOP and CHOP followed by radioimmunotherapy produced similar response rates, progression-free survival, and overall survival. Furthermore, there were no major differences in toxicities. The future role of radioimmunotherapy in induction and consolidation for follicular lymphoma remains to be determined. New strategies to enhance tumoricidal effects and reduce toxicity of radioimmunoconjugates are under study, including the use of radiosensitizers, fractionation, pretargeting, and production of humanized antibodies.

Interferon-α. The use of interferon (IFN)-α in follicular lymphoma has been extensively investigated both in combination with chemotherapy and as maintenance therapy, with varying results. In most studies, IFN-α was associated with a prolongation of remission, but not overall survival. A notable exception was the GELF86 trial, in which overall survival was prolonged. The Southwest Oncology Group (SWOG) reported results of a large phase III trial in which patients with indolent lymphomas were randomized to receive IFN-α or observation following induction with an intensive anthracycline-containing regimen and in some cases radiotherapy. Post-remission therapy did not prolong progression-free survival or overall survival.

Irradiation. Radiation therapy is not typically used in conjunction with systemic therapy. However, irradiation may be effective when used locally for palliation of symptomatic sites of disease. Abbreviated fractionated schedules (25 to 30 Gy in 2.5 to 3 Gy daily fractions, respectively) are often used. A low-dose regimen of 4 Gy in 2 fractions has been shown to be effective, with an overall response rate of approximately 80% in the palliation of symptoms, and is well tolerated. A phase III trial from the UK that compared 4 Gy with 24 Gy showed good symptom control with 4 Gy, but the progression-free rate is lower than with 24 Gy. Total-body irradiation, usually consisting of 12 Gy in 2 Gy fractions twice a day, is used as part of preparative regimens for bone marrow transplant.

Anti-idiotype vaccines. Lymphoma-specific idiotypes serve as tumor-specific antigens in follicular lymphoma and constitute the basis for vaccine therapy. In early vaccine trials, immunized patients who generated an anti-idiotype response experienced longer remissions than those who failed to mount a response. In phase I trials, vaccination resulted in tumor shrinkage in some patients, and in a phase II trial, anti-idiotype vaccine eliminated minimal residual disease detectable only by PCR after intensive chemotherapy.

A phase III randomized trial comparing vaccination plus KLH (keyhole limpet hemocyanin, a nonspecific immunostimulant) with KLH alone in previously untreated patients who achieved a complete remission with intensive anthracycline-containing combination chemotherapy was conducted. Patients who received the vaccine who were in complete remission for 6 months after intensive chemotherapy experienced a marginally significant prolongation of cancer-free survival. However, disease-free survival was prolonged significantly for those patients who received an IgM-Id but NOT for those who received an IgG-Id vaccine, compared with isotype controls. In contrast, two other placebo-controlled trials of anti-idiotype vaccination have shown no benefit. Compared with placebo, vaccination following induction chemotherapy with CVP, or induction immunotherapy with rituximab did not impact progression-free or overall survival. Differences in study design are likely responsible for the differences in outcomes among the trials. New directions in vaccination include idiotype-pulsed dendritic cell and membrane proteoliposomal vaccines.

Novel agents. New agents targeting specific molecular targets such as Bruton tyrosine kinase (BTK) receptor, the phosphoinositide 3–kinase pathway, the ubiquitin-proteasome pathway, histone deacetylase, the mammalian target of rapamycin, the microenvironment, and BCL2 have shown promise in the treatment of follicular lymphoma (Table 12). Novel antibody approaches to follicular lymphoma include new and improved anti-CD20s, antibodies that bind to alternative targets, antibody-drug conjugates, and radioimmunoconjugates.

Sidebar: Patients with indolent lymphoma refractory to both rituximab and an alkylating agent were treated with idelalisib daily, with promising results. Ninety percent of the 125 patients experienced a decrease in tumor burden with an overall response rate of 57% and median progression-free survival of 11 months. Responses were observed in all histologies and treatment was overall well-tolerated (Gopal AK et al: N Engl J Med 370:1008-1018, 2014).

SCT. The natural history of follicular lymphoma is characterized by response to therapy, but also by repeated relapses and progressively shorter and shorter remissions that ultimately result in death from progressive disease. Autologous and allogeneic SCTs are alternative strategies often associated with durable remissions that may impact overall survival. Unfortunately, immediate and long-term toxicities are significant and must be considered when assessing the appropriate role of transplant in the overall treatment plan for individual patients. Whether any of the new therapeutic strategies will prove to be as effective as autologous SCT in the relapsed setting remains to be seen.

Several groups have investigated the role of autologous SCT as consolidation therapy for patients in first complete or partial remission. Although progression-free survival may be prolonged, an impact on survival has not been demonstrated consistently. An increased incidence of secondary myelodysplasia following autologous SCT in first remission has reduced enthusiasm for this approach. Contemporary trials evaluating the role of autologous SCT for follicular lymphoma in first remission induced with rituximab-containing regimens are needed. The results of a German Lymphoma Study Group trial comparing IFN maintenance with myeloablative chemotherapy with autologous SCT after induction with CHOP or R-CHOP are awaited.

An alternative approach to consolidating complete and partial remissions achieved with conventional induction therapy is the use of a sequential high-dose chemotherapy program, which culminates in an autologous SCT. The Italian cooperative groups have reported results of a phase III randomized trial comparing R-CHOP for six cycles with sequential high-dose chemotherapy with autologous SCT. Again, there was a significant difference in event-free survival, but no difference in overall survival. Single-institution studies as well as analysis of registry data suggest that a tumor-free graft is an important determinant of outcome in follicular lymphoma. Administration of rituximab during stem cell mobilization provides an “in vivo” purge, reducing contamination of the autograft with malignant lymphocytes; however, a recent randomized trial showed no overall survival benefit.

Sidebar: Investigators from the United Kingdom randomized 280 relapsed/refractory follicular lymphoma patients in a factorial design who were undergoing autologous SCT to rituximab purging before SCT or rituximab maintenance after SCT. Pre-SCT rituximab purge had no effect on progression-free survival or overall survival, whereas rituximab maintenance was associated with improved 10-year progression-free survival (54% vs 37%, respectively; P = .01). However, overall survival was not improved with this treatment strategy (Pettengell R et al: J Clin Oncol 31:1624-1630, 2013).

Allogeneic SCT has been investigated primarily in young patients with HLA-identical sibling donors and extensive disease and/or marrow involvement. Low relapse rates suggest that this approach is potentially curative but is associated with treatment-related morbidity and mortality. Reduced-intensity transplant is based on the assumption that a graft-vs-lymphoma effect is operative and has the potential to cure follicular lymphoma. A recent update of nonmyeloablative allogeneic transplant for relapsed follicular lymphoma with a median follow-up of 107 months showed excellent long-term outcomes and is supportive of the trend to replace myeloablative conditioning regimens with regimens that are either reduced-intensity or strictly nonmyeloablative.

Overall treatment strategy

Whereas treatment choices were once limited to single or combination alkylator-based treatment, we now are faced with choosing among a wide variety of strategies. There are many unanswered questions that can only be addressed through well-designed clinical trials. Hence, whenever possible, every patient with follicular lymphoma should be enrolled in prospective clinical studies. In the absence of symptoms or other indications for treatment, patients should be observed. A combination of rituximab and chemotherapy is recommended in the absence of a clinical trial for those who require treatment, which may be followed by 2 years of maintenance rituximab. Select patients with comorbidities may be best served with rituximab-alone induction therapy. Radioimmunotherapy is a good option at the time of relapse, with transplant reserved for select patients in first or subsequent relapse.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

CLL/SLL (also see “Chronic Lymphocytic Leukemia and Hairy-Cell Leukemia” chapter) is a malignancy of small, round, B lymphocytes involving peripheral blood, bone marrow, and lymph nodes. The term “SLL” is reserved for cases in which there are no circulating malignant lymphocytes. SLL generally presents with lymph node and splenic involvement. Involvement of the bone marrow and peripheral blood may develop later in the course of disease. At the time of presentation, patients may be asymptomatic, complain of only fatigue, or have symptoms related to cytopenias (including autoimmune hemolytic anemia, lymphadenopathy, or splenomegaly).

The immunophenotype helps distinguish CLL/SLL from other B-cell leukemias/lymphomas, including mantle cell and leukemic forms of follicular lymphoma. Typically, the malignant lymphocytes stain weakly with surface immunoglobulin, CD20, CD22, and CD79b; they are CD5+, CD23+, and FMC7−. Cytogenetic abnormalities are detected in the majority of cases when FISH analysis is used. Trisomy 12, deletions at 13q14, and deletions at 11q22-23 are common. Many molecular markers of prognosis have been studied in CLL, including Zap-70, but their value in SLL is unknown.

Given the relatively small numbers of patients with SLL, they have generally been included in clinical trials of “indolent lymphoma.” Conventional alkylator-based regimens with rituximab as well as purine analogues and combinations including bendamustine have been used when patients become symptomatic. Anthracyclines have not been shown to benefit patients with CLL/SLL. When compared with follicular lymphoma, CLL/SLL is less likely to respond to rituximab as a single agent. Alemtuzumab (Campath), a potent therapy for CLL, is less effective in treating nodal disease than peripheral blood and bone marrow involvement. SCT, both autologous and allogeneic, has been studied in select patient populations but should be reserved for relapsed young patients with a good performance status.

As discussed in the CLL chapter, there are two additional CD20 monoclonal antibodies now Food and Drug Administration (FDA)-approved for the treatment of CLL (ie, ofatumumab [Arzerra] for CLL refractory to fludarabine and alemtuzumab; and obinutuzumab [Gazyva] for use in combination with chlorambucil for untreated CLL) and other novel therapeutic agents with very encouraging clinical activity (eg, the BTK inhibitor, ibrutinib [Imbruvica], and the PI3K delta inhibitor, idelalisib). An international randomized phase III study (RESONATE study) comparing ibrutinib with ofatumumab for patients with relapsed/refractory CLL or SLL was stopped early because an interim analysis showed a statistically significant improvement in progression-free survival and overall survival for patients receiving ibrutinib. O’Brien and colleagues recently reported results with single-agent ibrutinib in 29 older patients (age ≥ 70 years) with untreated CLL/SLL. At a median follow-up of approximately 2 years, the overall response rate was 71% (complete remission, 13%).

Sidebar: Goede and colleagues presented final results from the German CLL11 trial studying obinutuzumab plus chlorambucil in treatment-naive CLL patients with comorbidities. The phase III trial assigned 780 CLL patients with a Cumulative Illness Rating Scale score greater than 6 and/or an estimated creatinine clearance of less than 70 mL/min to obinutuzumab plus chlorambucil, rituximab plus chlorambucil, chlorambucil alone. Corresponding median progression-free survival was 26.7, 16.3, and 11.1 months, respectively (P < .0001). The overall survival was superior for obinutuzumab plus chlorambucil over chlorambucil (HR = 0.41; P = .002) (Goede V et al: N Engl J Med 370:1101-1110, 2014).

Splenic Marginal Zone Lymphoma

Splenic marginal zone lymphoma (SMZL) is a rare disorder accounting for less than 1% of NHLs. Clinically, this lymphoma most often presents as splenomegaly with splenic hilar node involvement but without peripheral adenopathy. The bone marrow is commonly involved, and malignant villous lymphocytes may be detected in the peripheral blood. Cytopenias are a common presenting feature, often related to hypersplenism and less frequently to an autoimmune process or marrow replacement. Sometimes confused with CLL or MCL, SMZL may be distinguished by its immunophenotype. Typically, cells are CD20+, CD79a+, CD5−, CD10−, CD23−, and CD43−. Staining for cyclin D1 is negative, excluding MCL. The absence of CD103 helps exclude hairy cell leukemia. Complex karyotypes are common. The clinical course is indolent. Cytopenias may respond to splenectomy with long-lasting remissions. High response rates have been reported with rituximab, and maintenance appears to delay relapse. Transformation to more aggressive histologies may occur. Fludarabine alone or with rituximab appears to be more effective than alkylators, which are relatively ineffective in this disease, but may be associated with significant toxicity.

Nodal Marginal Zone Lymphoma

Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell disorder that resembles lymph nodes involved by marginal zone lymphomas of extranodal or splenic origin without extranodal or splenic involvement. Lymphadenopathy (either localized or generalized) is the presenting complaint in most cases. Extranodal lymphoma may be uncovered in the evaluation of many cases of suspected NMZL. The clinical course is usually indolent, similar to that of other marginal zone lymphomas.

Extranodal Marginal Zone B-Cell Lymphoma of MALT Type

MALT lymphomas account for only 7% to 8% of B-cell lymphomas but nearly 50% of all gastric lymphomas. Although the GI tract is most often involved, other common sites include the lungs, head and neck, ocular adnexae, skin, thyroid, and breasts. There often is an associated history of autoimmune disorders, such as Sjögren syndrome or Hashimoto thyroiditis, or chronic inflammatory processes secondary to infectious agents (H pylori,B burgdorferi, or C psittaci). A form of MALT involving the small bowel (immunoproliferative small intestinal disease, previously known as α-heavy chain disease) has been associated with C jejuni. The majority of patients present with stage I or II disease. The frequency of bone marrow involvement appears to differ depending on the primary site of involvement. Multiple extranodal sites may be involved at the time of presentation. Transformation to a high-grade lymphoma may occur in approximately 8% of cases.

The malignant lymphocytes of MALT lymphoma are typically CD20+, CD79a+, CD5−, CD10−, and CD23−. The t(11;18)(q21;q21) is characteristic of MALT lymphomas, particularly those involving the stomach or lungs. The translocation creates a fusion between the MALT-1 gene, which is an essential regulator of BCL10–mediated NF-κB signaling, and the API2 gene, which inhibits apoptosis. This genetic abnormality is a marker of MALT lymphomas that do not respond to antibiotic therapy for H pylori infection, are associated with a more advanced stage, and do not transform into more aggressive NMZLs, SMZLs, or other types of lymphoma. Additional characteristic translocations have been discovered (Table 1), but their clinical significance is uncertain at this time.

Treatment of H pylori infection with triple therapy (eg, omeprazole, metronidazole, and clarithromycin) results in regression in the majority of early lesions. However, tumors invading beyond the submucosa and lesions with t(11;18) are associated with a failure to respond to H pylori eradication, deep penetration, and distant spread. Localized MALT gastric lymphoma that does not respond to antibiotics may be cured with local irradiation, with a field including the stomach and perigastric lymph nodes. This treatment is safe, extremely effective, and preserves the stomach. If local irradiation fails, chemotherapy or rituximab, and in some instances surgery, can be used. Alkylator-based therapy or purine analogues have been used with success for persistent or disseminated disease.

Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia is a disorder of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells, typically involving the bone marrow, lymph nodes, and spleen. It is usually associated with a serum monoclonal protein (usually IgM) with associated hyperviscosity or cryoglobulinemia. The clinical presentation is usually related to hyperviscosity with visual symptoms, stroke, or congestive heart failure. In approximately 10% of patients, peripheral neuropathies occur, which are related to reactivity of IgM with myelin-associated glycoprotein or gangliosides. An association with HCV infection has been demonstrated. Characteristically, the immunophenotypic analysis reveals surface and cytoplasmic immunoglobulin, usually IgM type, and B-cell–associated antigens (such as CD19, CD20, CD22, and CD79a). The malignant cells are CD5−, CD10−, and CD23−.

The clinical course is generally indolent. Asymptomatic patients may be observed. Plasmapheresis may be appropriate first therapy for those who present with hyperviscosity. The clinical status of the patient, not the level of the protein, determines when treatment is initiated. Choice of therapy depends on many individual factors, including age, comorbidities, and the particular indication for therapy. Rituximab and nucleoside analogues (cladribine and fludarabine) as well as the traditional oral alkylators have shown efficacy, whereas anthracyclines are not beneficial. Rituximab monotherapy may be associated with a rapid rise in IgM levels associated with increased serum viscosity requiring plasmapheresis. Combinations of these agents are also under study. Bortezomib, lenalidomide, and alemtuzumab have shown activity in Waldenström macroglobulinemia. SCT, both autologous and allogeneic, is being investigated in younger patients with relapsed or refractory disease. In addition, the BTK inhibitor ibrutinib is associated with encouraging clinical activity in patients with Waldenström macroglobulinemia, prompting expanded approval of this agent.

Sidebar: Ibrutinib was granted “breakthrough therapy designation” for Waldenström macroglobulinemia by the FDA January 29, 2015. The approval was based in part on a multicenter phase II study of ibrutinib 420 mg once daily for 63 patients with previously treated Waldenström macroglobulinemia. The overall response rate was 62% with median duration not reached and median time to response of 1.2 months. In addition, responses were impacted by mutations in CXCR4, but not MYD88 L265P, as predicted in laboratory studies (Cao Y et al. Br J Haematol 2015, Epub ahead of print; Cao Y et al: Leukemia 29:169-176, 2015).

Diffuse Large B-Cell Lymphoma

Clinical presentation

DLBCL makes up about one-third of the cases of NHL and is classified as a mature peripheral B-cell neoplasm by the WHO. The clinical presentation is variable, but generally patients present with either peripheral lymphadenopathy (neck, axillae) or enlarged nodes in the mediastinum, the mesenteric region, or the retroperitoneum. These sites predict symptoms, which may include chest pain; facial swelling and suffusion of the eyelids (SVC syndrome from mediastinal disease); abdominal discomfort, ascites (mesenteric), or back pain; or renal obstruction (retroperitoneal presentations). More than 30% of patients present with disease in extranodal sites, such as the GI tract (including Waldeyer ring), skin, bone marrow, sinuses, genitourinary tract, thyroid, and CNS. B symptoms, consisting of fever, sweats, and weight loss, are more common in DLBCL than in the indolent lymphomas and occur in about 30% of patients. The median age at presentation is 60 years.

Once the diagnosis is clearly established, staging studies are carried out to determine treatment and define parameters for follow-up. Generally, imaging studies of the chest, abdomen, and pelvis are obtained, and CT scans provide the most accurate anatomic information. Functional imaging using PET scans provides important information, including the diffferentiation between residual scar and active disease after treatment. Further, bone marrow biopsy and aspirate and LDH serum levels should be performed. Additional staging studies (eg, brain MRI, lumbar puncture, esophagogastroduodenoscopy) should be guided by clinical symptoms.

Pathology/immunology

The diagnosis should be made by incisional or excisional biopsy of an available lymph node, with adequate tissue for immunologic studies, such as flow cytometry or IHC, to identify the characteristic B-cell clonality (kappa or lambda restriction). The use of FNA or core biopsy should be discouraged; it is acceptable only when tissue cannot be safely obtained by other means and only if flow cytometry is used to help classify the disease (including ruling out composite lymphomas) and to distinguish it from other malignancies that may masquerade as lymphoma. In many cases of DLBCL, CD10 is present, indicating a germinal center origin. The CD20 antigen is present in almost all cases.

Markers for BCL2 and BCL6 help determine cell of origin (COO) and may offer prognostic information, although continued investigation and research are needed to refine the COO classification as demonstrated by the Gribben laboratory. In addition, molecular testing is encouraged because identification of c-MYC oncogene in DLBCL has been shown to predict for increased risk of CNS dissemination and overall inferior survival (compared with MYC–negative DLBCL). Two 2012 studies by Green et al and Johnson et al showed that DLBCL patients with MYC and BCL2 coexpression by IHC have a poorer prognosis when treated with R-CHOP therapy. This finding was corroborated in the International DLBCL Rituximab-CHOP Consortium Program; however, the most appropriate therapy for patients with “double-positive” protein expression is not known. Recent data have been published regarding the presence of molecular “double-hit” DLBCL, which is characterized by rearrangements in MYC with BCL2 and/or BCL6.

Sidebar: A large, multicenter retrospective study examined features and outcomes of 311 patients with untreated double-hit lymphoma. At 2 years, 40% of patients remained disease-free and 49% were alive. Intensive induction was associated with improved progression-free survival, but not overall survival. Further, a double-hit lymphoma prognostic risk score was developed (Petrich AM et al: Blood 124:2354-2361, 2014).

Prognostic factors

Clinical predictors of response have been identified and are now widely used to help design therapeutic plans and clinical trials. These predictors include patient age (younger than or older than 60 years), performance status (0, 1 vs 2-4), number of extranodal sites (more than two), Ann Arbor stage (I or II vs III or IV), and serum LDH level (higher than normal; Table 6). Older patients, higher stage, poorer performance status, higher number of extranodal sites, and higher LDH level all predict a worse outcome, and this model has been validated in more than 3,000 patients. These parameters have been called the IPI; this index is used to plan therapy and clinical trials in the United States and abroad and may be used to predict survival. Updated analyses of the IPI in the post-rituximab era have validated the IPI as an important prognostic tool (Table 13).

Genomics have also been used to help predict outcome on the basis of molecular signature (see subsection on Molecular profiling). This molecular system provides prognostic information independent of the IPI.

Treatment

Before the 1970s, most patients with stage I/II large cell lymphoma (intermediate grade in the Working Formulation) were treated with irradiation alone, with overall cure rates of 40% to 50%. Patients with pathologically favorable stage I/II disease had even better outcomes, but relapse rates, even in these patients, were still 20% to 30%. Pathologic staging, therefore, selected a group suitable for irradiation alone. This approach is no longer appropriate, in view of the success of combined chemotherapy and irradiation in clinically staged patients.

TABLE 13: Outcomes according to International Prognostic Index (IPI) factors and the NCCN-IPI in patients with de novo DLBCL treated with R-CHOP in British Columbia Cancer Agency database

Coiffier et al (N Engl J Med 2000) found that the addition of rituximab improved results in elderly patients with DLBCL, and recent data confirm these observations for younger patients as well. For patients with clinical stage I or II disease (by the Ann Arbor criteria), most studies suggest that chemotherapy (CHOP) with rituximab for three or four cycles followed by localized radiation therapy is preferred. Excellent local and systemic tumor control is obtained with combined-modality therapy.

In an Eastern Cooperative Oncology Group (ECOG) phase III trial, Horning et al showed that eight cycles of CHOP and irradiation produced a 10-year disease-free survival rate of 57%, compared with 46% with CHOP alone (P = .04). Overall survival was 64% vs 60%, respectively (P = .23), and time to disease progression was 73% vs 63%, respectively (P = .07).

Miller et al showed that CHOP (three cycles of CHOP and irradiation) produced a progression-free survival at 5 years of 77%, vs 64% for eight cycles of CHOP alone (P = .03). Overall survival at 5 years was 82% vs 72%, respectively (P = .02). Update of this SWOG study was reported by Miller et al, with an 8.2-year median follow-up. The 5-year estimates for CHOP for three cycles plus irradiation vs CHOP for eight cycles remained unchanged. Kaplan-Meier estimates, however, now show overlapping curves at 7 years for failure-free survival and 9 years for overall survival. The treatment advantage for CHOP (for three cycles plus irradiation) for the first 7 to 9 years was diminished because of excess late relapses and NHL deaths occurring between 5 and 10 years. Patients with good IPI risk factors had a 5-year overall survival of 94%; patients with one adverse risk factor had an overall survival of 70%; those with three adverse risk factors had a 5-year survival of 50%.

These results were confirmed by a single-arm (doxorubicin-containing chemotherapy) approach followed by IFRT conducted by the British Columbia Cancer Agency. However, two reports from European investigators question the value of consolidation irradiation in early-stage disease. These studies did not use rituximab or FDG-PET staging, and details on the irradiation technique used were not available. The necessity of consolidation radiation therapy after complete response to R-CHOP chemotherapy is now being tested in a randomized study in Germany (the UNFOLDER trial).

Until further studies define the optimal therapy for stages IA to IIA DLBCL (nonbulky), many investigators consider three or four cycles of R-CHOP and IFRT the initial treatment of choice. For patients with bulky disease, a minimum of six cycles of R-CHOP is typically administered. Irradiation doses of 30 to 36 Gy, delivered in 1.75 to 1.8 Gy over 3 to 4 weeks after completion of systemic therapy, appear to be adequate. Radiation fields usually include involved lymph node sites or an involved extranodal site and its immediate lymph node drainage areas. Volumetric definitions of radiation target volumes are now used with 3-dimensional CT planning, and when gross target volume, clinical target volume, and planning target volume are outlined, such planning methods to treat the involved site(s) are now termed “involved-site radiation therapy” (ISRT). For the most common presentations of stage I-II lymphoma, the disease is encompassed in a planning target volume with acceptable toxicity.

Disease site or potential toxicities may influence the treatment plan:

• Lymphomas of the head and neck may be managed with chemotherapy alone to avoid the acute mucositis and long-term xerostomia associated with radiation therapy fields that are large and include both parotid glands. Alternatively, precise radiation therapy techniques can be employed with intentional sparing of salivary glands, using IMRT.

• Fully resected gastric or small intestinal lymphoma may be treated with chemotherapy alone. Patients at high risk for perforation or life-threatening hemorrhage may require surgical resection. Alternatively, chemotherapy followed by local irradiation allows gastric preservation and is preferred in most patients.

For patients with advanced stage (III or IV) disease, CHOP continues to be the standard combined with rituximab for six cycles. Preliminary results from three randomized studies using “dose-dense” therapy (ie, shortening the interval between cycles from 3 weeks to 2 weeks with growth factor support) have shown no benefit to this strategy. Mature data are needed to confirm these preliminary results. The addition of rituximab to CHOP chemotherapy has been shown to be associated with improved response rate, disease-free survival, and overall survival. There appears to be no advantage to maintenance therapy with rituximab in this setting as long as rituximab is included in the induction. Responses are seen in upward of 90% of patients, and approximately 60% to 65% of patients are cured. Several studies have shown that early complete remission by PET (ie, after two or three cycles) predicts for favorable outcome, while persistent metabolic uptake predicts for high risk of relapse. Further, phase II studies have shown that modification of chemotherapy (eg, from CHOP to ICE [ifosfamide, carboplatin, etoposide]) for patients with positive early PET findings may improve outcomes. However, this is not recommended outside of a clinical trial, in part because of the poor reproducibility in the interpretation of PET scans and nonrandomized data. Data published by the German High-Grade Non-Hodgkin Lymphoma Study Group in successive DLBLC studies have suggested that sex and age may impact the benefit to rituximab therapy (see sidebar). Continued prospective studies are needed to define the most optimal dose and dosing schedule of rituximab (based in part on age and sex).

Sidebar: The German High-Grade Non-Hodgkin Lymphoma Group showed that compared with elderly women, all other subgroups had significantly faster clearance of rituximab and thus appear to be suboptimally dosed when rituximab is given at 375 mg/m2 (Pfreundschuh M et al: Blood 123:640-646, 2014). They followed this observation with the prospective SMARTE-R-CHOP-14 trial, which showed improved pharmacokinetics in older men (Pfreundschuh M et al: J Clin Oncol 32:4127-4133, 2014).

As described before, DLBCL patients with “double-positive” MYC and BCL2 protein expression and especially molecular “double-hit” DLBCL (MYC with BCL2 and/or BCL6) have inferior outcomes when treated with R-CHOP therapy. Ideal therapy for these patient populations is not known. Continued treatment strategies, such as more intensive chemotherapy (eg, DA-EPOCH-R [dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin with rituximab]), consolidative therapy (eg, autologous SCT), and the integration of rational targeted therapeutic agents, continue to be explored.

For patients who either do not have a complete remission or who relapse, alternative therapies are possible, but long-term responses have been seen mostly with autologous or allogeneic SCT. The impact of posttransplant therapy is not standard, although several investigational efforts are examining this. Patients who do not have responsive disease before SCT generally do poorly. The IPI has been used to predict outcome for transplant in DLBCL. The role of autologous SCT for high-risk patients remains open to debate. A randomized clinical trial of early vs delayed high-dose therapy for patients with high- and high-intermediate–risk diffuse aggressive lymphoma conducted by the US intergroup showed no benefit to this approach; however, the subgroup of patients with high risk according to the IPI may not have been powered to detect a small difference. Outside of a clinical trial, consolidative SCT is not recommended. Investigational treatments include novel antibodies, radioimmunotherapy, single-agent chemotherapy drugs, and the integration of novel therapeutic agents (eg, ibrutinib, lenalidomide). Nonmyeloablative SCT continues to be evaluated in patients with recurrent or refractory disease.

Some investigators believe that irradiation for stages III and IV (advanced or extensive) DLBCL may be added after the completion of definitive chemotherapy if there is localized residual disease, to improve local tumor control. Irradiation may also be delivered after chemotherapy to areas of initially bulky disease, again to enhance local tumor control. These recommendations are based on the observation that when DLBCL relapses after definitive chemotherapy, it usually does so in initially involved or bulky areas of disease. The benefits and potential adverse effects of irradiation should be weighed against the use of alternative chemotherapy salvage regimens.

Mantle Cell Lymphoma

Clinical presentation

By comparison with patients with low-grade NHL, patients with MCL are older (median age, 64 years), mostly male (75%), and more likely to have peripheral blood involvement (about 30%) and extranodal involvement (mostly the GI tract and CNS, as discussed below). The clinical course in MCL is characterized by features of the aggressive lymphomas (an aggressive course) and the indolent lymphomas (frequent recurrences). The disease is often widespread at diagnosis, and marrow involvement and splenomegaly are common. GI tract involvement is also common, and many centers suggest evaluation of the GI tract at the time of diagnosis. CNS recurrences are frequent (up to 20%), but isolated CNS disease is a rare occurrence. Leukemic presentations are not uncommon, especially in patients with “blastic” MCL.

It is also important to recognize that a subset of MCL patients may present with indolent disease and may not warrant immediate therapy. Among 97 MCL patients seen over a 10-year period at Cornell, Martin and colleagues (J Clin Oncol 2009) observed 32% of patients more than 3 months before start of systemic therapy. Median time to treatment for this group of patients was 12 months (range, 4 to 128 months). Better performance status and lower-risk IPI scores were characteristic of the patients who could be observed. Altogether, this finding suggests that a deferred approach to treatment is acceptable in a select group of patients with MCL.

Pathology/immunology

This disorder was originally classified as diffuse, small, cleaved lymphoma by the REAL classification and represents less than 10% of all NHLs. In this disease, a homogeneous population of small lymphoid cells with irregular nuclear borders arises from and expands the mantle zone surrounding the germinal centers of the lymph nodes, spreading diffusely through the node as the germinal centers are overrun. The lymphocytes express IgM or IgD, as in CLL, but in much greater density. It was recognized that the cells carry a translocation of the long arms of chromosomes 11 and 14, notated as t(11;14)(q13;q23). This molecular event juxtaposes the BCL1 gene on chromosome 11 to the immunoglobulin heavy-chain gene on chromosome 14, leading to overexpression of BCL1. This gene encodes the cell-cycle regulatory protein cyclin D1, which is believed to play a role in checkpoint control in DNA synthesis. The immunophenotype is characteristic, and MCLs are usually CD5+, CD20+, CD10−, CD23−, and FMC7+. This immunophenotype is similar to that seen with CLL/SLL, except that CD23 is most often expressed in CLL/SLL but usually is not expressed in MCL. The key to the diagnosis is the demonstration in tumor tissue or peripheral blood of the t(11;14) by FISH or the cyclin D1 protein by IHC. Inactivation of the ATM gene has been described in MCL. Data also show that MCL cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d), suggesting a relationship with the stromal environment.

The role of SOX11 in MCL biology has been debated, and its importance as a prognostic factor remains uncertain. Vegliante and colleagues found that SOX11 directory regulates the expression of PAX5, a transcription factor that maintains B-cell identity and represses plasma cell differentiation, thus preventing MCL cells from completing their normal differentiation process. These data suggest that the development of MCL may be related to a combination of cyclin D1 overexpression, deregulation of cell proliferation, and the block of normal B-cell differentiation, which prevents further development through the SOX11-PAX5-BLIMP-1 regulatory axis.

Sidebar: Investigators evaluated t(11;14)-positive B-PLL patients and 6 t(11;14)-negative B-PLL patients. There was high similarity in immunophenotype and gene expression profile between t(11;14)-positive B-PLL and MCL. Furthermore, the t(11;14)-negative B-PLL cases appeared as a subgroup of MCL, while a third group clustered close to nodal MCL and was associated with short survival (van der Velden VH et al: Blood124:412-419, 2014).

Treatment

The NCCN guidelines recommend clinical trials for patients with MCL (there is no “standard” therapy); however, a number of exciting breakthroughs have been seen recently in the treatment of MCL. Responses to aggressive chemotherapy alone (CHOP or R-CHOP) are seen, but patients relapse frequently, and median survival is short (typically <16 months). Recent data suggest an advantage to autologous SCT while patients are in first remission, but more data are required to validate these results. Patients who have relapsed after autologous SCT have been successfully “rescued” and potentially cured by allogeneic SCT.

Sidebar: External validation of the MIPI was performed on 958 patients with MCL who were treated in two recent randomized trials of the European MCL Network. Five-year overall survival rates in MIPI low-, intermediate-, and high-risk groups were 83%, 63%, and 34%, respectively. The prognostic significance was independent of patient age or treatment strategy (Hoster E et al: J Clin Oncol 32:1338-1346, 2014).

Sidebar: Recently Robak and colleagues described the substitution of bortezomib for vincristine in R-CHOP (VR-CAP) in patents with newly diagnosed MCL. In a randomized study, they reported an improvement in the primary endpoint of the study, which was progression-free survival, from 16.1 months to 30.7 months (HR = 0.51; P < .001). Secondary endpoints, including complete response rates (42% vs 53%), duration of CR (18 months vs 42.1 months), median treatment-free interval (20.5 months vs 40.6 months), and 4-year overall survival rate (54% vs 64%), were all in favor of the VR-CAP regimen over the R-CHOP regimen. These studies need further validation. Furthermore, the role of maintenance therapy with rituximab or consolidation with SCT were not addressed in this study (Robak T et al: N Engl J Med 372:944-953, 2015).

A number of studies over the past 5 to 10 years have examined intensive treatment strategies for patients with newly diagnosed MCL. Investigators have shown that aggressive hyperfractionated chemotherapy with rituximab (R-hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone]) may result in long-term responses in patients with MCL.

The Nordic group compared their prior experience (1996-2000) using a high-dose CHOP regimen for four cycles followed by an autologous SCT with BEAM (carmustine [BiCNU], etoposide, cytarabine [Ara-C], methotrexate) or BEAC (carmustine [BiCNU], etoposide, cytarabine [Ara-C], cyclophosphamide) conditioning with a newer regimen (2000-2006). Patients were then followed up using patient-specific primers as markers for molecular relapse; those who showed molecular recurrence were treated with rituximab preemptively. Only morphologic relapse was considered a “relapse” for the purposes of this trial. The results of the two trials were compared and showed that 5-year event-free survival improved from 15% to 41% and overall survival, from 63% to 75%. Further studies are needed to verify these data.

A number of MCL patients cannot tolerate aggressive induction therapeutic regimens such as hyper-CVAD/Ara-C-MTX or autologous SCT. Thus, more tolerable treatment regimens are needed. The combination of bendamustine and rituximab (BR) has been shown to be a well-tolerated and an active treatment regimen. A subset of patients from the Study group indolent Lymphomas (StiL) study had MCL; the median progression-free survival for patients treated with BR was 35 months compared with 22 months for patients who received R-CHOP (P = .004). The Mayo Clinc has reported an additional low-intensity chemotherapeutic regimen for frontline treatment of MCL that includes cladribine.

The potential benefit of maintenance therapy for MCL, in particular rituximab, has been hotly debated. The German Mantle Cell Group randomized 560 older MCL patients to R-CHOP or to fludarabine, cyclophosphamide, and rituximab induction therapy, which was followed by a second randomization to maintenance therapy with either rituximab or IFN. Results showed that maintenance rituximab resulted in better progression-free survival compared with IFN in patients who were initially treated with R-CHOP but not in patients who were treated with purine analogue–containing regimens. Moreover, among patients treated with R-CHOP induction therapy, maintenance therapy with rituximab significantly improved overall survival (4-year overall survival rates of 87% vs 63% with IFN; P = .005).

There have been several recent clinical breakthroughs in MCL. The oral immunomodulatory agent, lenalidomide, was FDA-approved in June 2013 for the treatment of patients with MCL whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. This approval was based on the results of the single-arm phase II EMERGE study of 134 patients with relapsed/refractory MCL. The overall response rate was 28%, with median time to response of 2.2 months and a median duration of response of 16.6 months.

More recently, the oral BTK inhibitor, ibrutinib, was approved by the FDA for patients with relapsed/refractory MCL who have received at least one prior therapy. Wang and colleagues from MD Anderson Cancer Center reported an overall response rate of 68% in heavily pretreated MCL patients; the median duration of response was 15.3 months. There are now multiple ongoing studies examining both of these targeted treatment agents, in addition to bortezomib (FDA-approved in 2006 for relapsed/refractory MCL) and other therapeutics, as a part of up-front therapy for MCL (eg, NCT01415752 and NCT01776840). All of these novel therapeutics have the potential to change the landscape of treatment approaches for MCL.

Burkitt and Burkitt-Like Lymphoma

Clinical presentation

These diseases present as three distinct clinical entities: endemic, sporadic, and immunodeficiency-related types. Endemic Burkitt lymphoma most often presents in young children or adolescents with large nodes in the neck, often involving the maxilla or mandible. These cases are most often seen in equatorial Africa and follow the distribution of endemic malaria, hence its designation as “endemic Burkitt lymphoma.” In American, or sporadic, Burkitt or Burkitt-like lymphomas, the disease presents in the abdomen and extranodal sites, especially in the GI tract. Sporadic Burkitt lymphoma accounts for 1% to 2% of all adult lymphomas in Western Europe and the United States. The immunodeficiency type is seen in the setting of HIV infection but can be seen in patients with CD4 cell counts greater than 200/µL. In both endemic and sporadic Burkitt and Burkitt-like lymphomas, males are affected more often than females.

The LDH level is often elevated, owing to the high turnover rate of these cells and the bulk of disease. The bone marrow and CNS are often involved, and if not involved initially, they are at risk, so CNS prophylaxis is needed. A staging system for Burkitt and Burkitt-like lymphomas has been developed by Murphy and associates.

Pathology/immunology

These lymphomas are the most rapidly proliferating (doubling time of 25 hours) NHLs. Under the microscope, it is difficult to distinguish Burkitt from Burkitt-like lymphomas and from the B-cell French-American-British L3 variant of acute lymphoblastic leukemia. Indeed, the WHO classification recognizes the lymphoma and leukemic phases as a single entity, a mature B-cell neoplasm. The disease is characterized by medium-sized cells with an abundant basophilic cytoplasm with lipid vacuoles. There are round nuclei with clumped chromatin and multiple nucleoli; a diffuse pattern of infiltration is seen and is classic for Burkitt lymphoma. The numerous macrophages that are usually seen in the lymph node biopsy specimens give rise to the so-called starry-sky appearance.

The proliferative rate of this tumor is high, and there are frequent apoptotic cells. In the Burkitt-like variant, there is greater pleomorphism in nuclear size and shape, and the nuclei have fewer nucleoli. There is a low level of concordance among pathologists (about 53%) when they attempt to distinguish Burkitt from Burkitt-like lymphomas, and even by clinical criteria, that distinction is difficult. The cells express surface IgM, CD19, CD20, CD22, CD10, and CD79a and do not express CD5, CD23, and TdT. BCL6, a zinc finger protein, is usually expressed. The major consideration in the differential diagnosis is precursor B-cell lymphoma/leukemia, which in contrast expresses TdT; surface immunoglobulin is mostly negative. CD20 may also be negative in this disorder. In Burkitt lymphoma, the expression of CD10 and BCL6 protein suggests that these cells originate from the germinal center and, indeed, this is confirmed by sequence analysis of the immunoglobulin variable heavy-chain and light-chain genes. Somatic hypermutation of these genes has been described. Gene expression and microRNA profiles from each of the Burkitt lymphoma subtypes are homogeneous and distinct compared with DLBCL.

Genetics

The distinguishing genetic abnormality in Burkitt lymphoma is overexpression of the c-myc oncogene; in 80% of cases, this abnormality results from a balanced translocation between chromosomes 8 and 14, notated as t(8;14), where the c-myc oncogene on chromosome 8 is juxtaposed to immunoglobulin heavy-chain enhancer elements on chromosome 14. In the remaining 20% of cases, there are other translocations, including t(2;8)(p12;q24) and t(8;22)(q24;q11). There have been different breakpoints identified in Burkitt lymphoma, and they have been associated with the sporadic and immunodeficiency subtypes.

Sidebar: An analysis of cytogenetic and molecular features in Burkitt lymphoma cell lines and patient samples has recently been completed by Murga Penas et al. It appears that most of the cell lines remained stable over years of passages. The most frequent structural changes were dup (1q) and del (13q), and the most frequent numerical changes were +7 and +13. Interestingly, the frequency of 1q gains and 13q losses was higher in the EBV-negative than in EBV-positive Burkitt cell lines (Murga Penas EM et al: Genes Chromosomes Cancer 53:497-515, 2014).

Sidebar: Recent studies identified MYC-negative Burkitt-like lymphoma, characterized by a recurrent focal homozygous deletion in 11q24.2-q24.3, including the ETS1 gene, which was shown to be mutated in 4 of 16 cases that were investigated. These data suggest the existence of a B-cell lymphoma similar to Burkitt lymphoma that is identified by deregulation of genes in 11q (Salaverria I et al: Blood 123:1187-1198, 2014).

EBV

EBV, a member of the herpesvirus family, has the ability to infect resting B cells and transform them into proliferating blasts, most likely by bypassing antigens on lymphocytes and activating signaling molecules. By contrast, certain viruses (HCV) and bacteria (H pylori) may cause lymphoma by activating lymphocytes in an antigen-specific manner. EBV infection results in a polyclonal proliferation of lymphoblasts that are latently infected with the virus, as opposed to the infection seen in infectious mononucleosis, which is a lytic infection. This process is regulated by the expression of up to nine latent viral proteins, which are under the control of the transcription factor EBV nuclear antigen 2. It appears that the type and result of EBV infection in lymphoid tissue are controlled by various “growth programs,” each causing expression of different viral proteins, which then determine the fate of the infected cell. These in vitro events are different from what occurs in healthy carriers of EBV (up to 90% of the population have been exposed), where the viral proteins are not expressed because all of the latently infected cells are resting memory B cells.

Although EBV was found in patients with Burkitt lymphoma over 40 years ago, the role of EBV in the disease still remains uncertain. The exact role of c-myc overexpression in the pathogenesis of the disease is also not known, but c-myc is known to play a role in cell-cycle progression and cellular transformation. EBV is found in more than 95% of cases of “endemic Burkitt lymphoma,” which occurs in Africa, but its role in the pathogenesis of the disease is still not clear. The reason therapy with antiviral agents (ganciclovir or acyclovir) cannot be used to treat EBV-associated lymphomas is that the required thymidine kinase gene is not expressed in latent EBV infection. Recent studies using the small molecule arginine butyrate, to up-regulate the thymidine kinase gene and protein expression, with concomitant antiviral antibiotics have met with some success.

Treatment

Patients must be treated quickly after diagnosis, which should be made on a full biopsy so that adequate tissue is obtained. Tumor lysis syndrome occurs most often with Burkitt lymphoma, and attempts to reduce uric acid production with allopurinol or to degrade it with the enzyme rasburicase (Elitek) should be part of the management, as should aggressive hydration. Patients should be managed in a facility with access to support such as urgent dialysis, because it may be necessary if tumor lysis syndrome occurs. In addition, it is often beneficial to institute a “pre-phase” of therapy using pulse steroids with lower-dose fractionated cyclophosphamide with or without vincristine.

Treatment has typically included aggressive chemotherapy, with anthracyclines and cyclophosphamide as the cornerstone. Regimens incorporating hyperfractionated cyclophosphamide such as hyper-CVAD, developed by Murphy and adopted by the M. D. Anderson group, have been used. Other published regimens include CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose Ara-C) and the French regimen, which incorporate intensive therapy given weekly in various combinations, and intrathecal chemotherapy and systemic high-dose methotrexate or high-dose Ara-C to facilitate CNS penetration. Evens et al have shown excellent response rates and disease-free survival in patients treated with a modified CODOX-M/IVAC regimen that substituted Doxil for Adriamycin and integrated high-dose rituximab. In addition, excellent outcomes were recently reported for rituximab combined with DA-EPOCH therapy.

The treatment of Burkitt lymphoma in adults has been reviewed recently by Jacobson and LaCasce.

Sidebar: It has become clear now that rituximab should be included as a part of the aggressive regimens that are used to treat Burkitt lymphoma (Wildes TM et al: Ther Adv Hematol 5:3-12, 2014; Shahbazi S et al: Cancer Biol Ther 15:1117-1119, 2014; Rizzieri DA et al: Br J Haematol 165:102-111, 2014).

Primary Mediastinal Large B-Cell Lymphoma

Clinical presentation

Primary mediastinal large B-cell lymphoma (PMLBCL) occurs most often in young women (female to male ratio is 2:1) who present with mediastinal masses only. These masses are usually bulky and often invade surrounding structures, such as the pleura, lungs, pericardium, and chest wall, but disease is infrequently found outside the chest cavity. At recurrence, however, extranodal sites such as the lungs, adrenal glands, liver, or kidneys may be involved. Because of the location and bulk of the disease, patients complain of chest pain, cough, and shortness of breath and are often found to have SVC syndrome. This can be subtle, with unexplained breast enlargement the only symptom in some cases. The diagnosis can be delayed if the clinician does not recognize the signs and symptoms of SVC syndrome. This clinical presentation is similar to that of classic Hodgkin lymphoma, and indeed, that is the primary differential diagnostic consideration when these patients are evaluated.

Pathology/immunology

The pathology is characterized by a diffuse proliferation of large cells with clear cytoplasm, often accompanied by extensive sclerosis. The cells are mostly of B-cell origin and express CD20 and other B-cell markers but do not express surface immunoglobulin (Ig). Indeed, the discordant expression of CD79a and Ig expression are distinguishing features of PMLBCL. There are data that describe gains of chromosomal material in tissue specimens, most often 2p, 9p, 12q, and Xq. The rel, mal, and fig1 (IL4 gene) oncogenes are overexpressed in tissue specimens. Ig genes have a high level of somatic hypermutation. All of these observations suggest that this entity is unique, especially compared with B-cell lymphomas that arise in peripheral nodes. IL-13 expression and downstream effectors of IL-13 signaling pathways are overexpressed, along with tumor necrosis factor (TNF) family members and TNF receptor–associated factor-1.

Sidebar: Recenlty, Shi et al described the expression of the programmed cell death ligand PDL-2 in primary mediastinal B-cell lymphoma; mutations of PTPN1 have also been described by Gunawardana et al. In the Gunawardana study, the mutations were found in 17 of 77 cases (22%), while the same mutations were found in 6 of 20 of Hodgkin lymphoma cases (20%). The consequences of these mutations are reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. These biology studies identify potential therapeutic targets in PMLBCL (Shi M et al: Am J Surg Pathol 38:1715-1723, 2014; Gunawardana J et al: Nat Genet 46:329-335, 2014).

The overexpression of the rel oncogene, previously described, has been associated almost exclusively with the nucleus, consistent with NF-κB pathway activation, and mal gene overexpression has been confirmed in gene array studies. These data help us to reorder our thinking about these clinically unique lymphomas and to begin to build a molecular story that is consistent with the clinical observation that PMLBCL is more like classic Hodgkin lymphoma than like DLBCL. Furthermore, the observations that certain signaling pathways are involved provide a rationale to attack these pathways specifically in a targeted approach.

As we learn more about this disorder, similarities to classic Hodgkin lymphoma become more clear.

The WHO recognizes a category as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma, which is commonly referred to as gray zone lymphoma. A recent prospective study using DA-EPOCH-R for patients with gray zone lymphoma was reported (Sidebar).

Sidebar: The NCI group treated 24 patients with mediastinal gray zone lymphoma in a prospective study using infusional DA-EPOCH-R. The event-free survival and overall survival rates for these patients were 62% and 74%, respectively, which were more modest than were outcomes for patients with primary mediastinal DLBCL (Wilson WH et al: Blood 124:1563-1569, 2014).

Treatment

The clinical course is variable; some report a poor outcome with conventional, CHOP-based chemotherapy regimens and irradiation, and some report an excellent outcome. It seems clear that bulk of disease and LDH level are important prognostic factors and that prediction of the outcome by the IPI is useful. A variety of chemotherapy regimens have been evaluated, including CHOP and MACOP-B/VACOP-B (methotrexate or etoposide, Adriamycin, [doxorubicin], cyclophosphamide, Oncovin [vincristine], prednisone, bleomycin), and more recently rituximab has been incorporated into the management. Usually, radiation therapy is a part of the initial treatment; however, recent data suggest that radiation therapy may not be necessary in all patients. In general, patients receive anthracycline-containing chemotherapy with rituximab, and after four to six courses, radiation therapy may be given to patients with bulky disease. There is currently one randomized trial, conducted by the International Extranodal Lymphoma Study Group (IELSG), that compared radiation therapy with no radiation therapy in this setting; complete metabolic response was achieved in patients who completed R-CHOP chemotherapy (or equivalent). However, in the subgroup of patients with PMLBCL treated with DA-EPOCH-R (n = 51), radiation was not necessary to achieve high rates of long-term disease-free survival and was comparable to that found in historical data using radiation. PET scanning and early PET response may influence the use of consolidation radiation therapy in the future.

Sidebar: Recently, the role of PET imaging in the management of patients with PMBCL has been evaluated and is the subject of active clinical trials. In 2015, there were three studies that evaluated PET scans in PMBCL and the conclusion of all was the same: the PET scan as an interim or end of treatment test had excellent negative predictive value, but positive PET scans need to be confirmed by biopsy before second-line therapy is instituted. The role of PET in the management of patients with lymphoma is in evolution, and further studies standardizing response criteria are still needed (Nagle SJ et al: Cancer Med 4:7-15, 2015; Vassilakopoulos TP et al: Leuk Lymphoma 56:3-5, 2015; Cheah CY et al: Leuk Lymphoma 56:49-56, 2015).

Peripheral T-Cell Lymphoma, Unspecified

PTCL, unspecified is predominantly a nodal lymphoma that represents the most common T-cell lymphoma subtype in Western countries, accounting for approximately 50% to 60% of T-cell lymphomas and 5% to 7% of all NHLs. PTCL usually affects male adults (male to female ratio, 1.9:1), with a median age of 61 years (range, 17 to 90 years); 25% of patients present in stage I or IIE, 12% in stage III, and 63% in stage IV. Patients with PTCL commonly present with unfavorable characteristics, including B symptoms (40%), elevated LDH level (66%), bulky tumor 10 cm or larger (11%), nonambulatory performance status (29%), and extranodal disease (56%), leading to the majority of patients (53%) falling into the unfavorable IPI category (score of 3 to 5). In addition, gene signature clusters predictive of survival have been identified.

Most T-cell NHL patients are treated in the same manner as aggressive B-cell patients, with anthracycline-based combination chemotherapy such as CHOP; however, the results are inferior. Randomized trials comparing CHOP with other combination regimens have failed to identify a superior regimen. Rituximab should not be included in the treatment of PTCL (unless other conditions such as immune thrombocytopenic purpura exist), because CD20 is not expressed.

Denileukin diftitox is a novel recombinant fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domains of diphtheria toxin with recombinant IL-2 (CD25 receptor); it has been studied mostly in cutaneous T-cell NHL, although clinical benefit has been reported in other T-cell NHL patients. The histone deacetylase inhibitors romidepsin (Istodax) and belinostat (Beleodaq) have shown activity against PTCL and are FDA-approved medications for patients who have received at least one prior therapy. The novel antifolate pralatrexate (Folotyn) is also FDA-approved for the treatment of patients with relapsed or refractory PTCL, brentuximab vedotin (Adcetris) has efficacy in tumors expressing CD30, while recent phase I/II studies of an Aurora-A kinase inhibitor, alisertib, have shown activity against PTCL. In addition, both gemcitabine (Gemzar) and Doxil are active agents against PTCL. Recently, the Center for International Blood and Marrow Transplant Research examined and demonstrated a role of SCT for patients with newly diagnosed and relapsed/refractory PTCL.

Sidebar: Belinostat, a histone deacetylase inhibitor (HDACi), was approved by the FDA in 2014 for use in patients with relapsed/refractory PTCL. An overall response rate of 25.8% was seen in a clinical study involving 120 patients with relpased or refractory PTCL. Common adverse effects were similar to those seen with other previously approved HDACi agents (O’Connor OA et al: J Clin Oncol 31(suppl):abstract 8507, 2013); Foss F et al: Br J Haematol 168:811-819, 2015).

Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL), also known as angioimmunoblastic lymphadenopathy with dysproteinemia, is one of the more common T-cell lymphomas, accounting for 15% to 20% of cases and 3% to 4% of all lymphomas. Pathologically, AITL has distinct features, with a diffuse polymorphous infiltrate, prominent arborizing blood vessels, perivascular proliferation of follicular dendritic cells, and the presence of large B-cell blasts often infected with EBV. The malignant cells are mature follicular helper CD4 α β T cells. The mean age at presentation is 57 to 65 years, with a slight male predominance, and the majority of patients present with stage III or IV disease. AITL is commonly a systemic disease with nodal involvement with various associated disease features, such as organomegaly, B symptoms (50% to 70%), rash, pruritus, pleural effusions, arthritis, eosinophilia, and varied immunologic abnormalities (positive Coombs test, cold agglutinins, hemolytic anemia, antinuclear antibodies, rheumatoid factors, cryoglobulins, and polyclonal hypergammaglobulinemia).

Spontaneous disease regression is seen on rare occasions, although AITL typically follows an aggressive clinical course. Treatment with anthracycline-based combination chemotherapy results in complete remission rates of 50% to 70% for AITL patients, although only 10% to 30% of patients are long-term survivors.

In one prospective, nonrandomized, multicenter study, patients with newly diagnosed “stable” AITL were treated with prednisone with or without combination chemotherapy. Patients who had a complete remission after initial treatment with prednisone received no further treatment. Patients with relapsed/refractory disease were given combination chemotherapy. Patients who had “life-threatening” disease at diagnosis also received combination chemotherapy initially. The complete remission rate was 29% for patients who received single-agent prednisone, whereas the complete remission rates for patients with relapsed/refractory disease or patients who initially received combination chemotherapy were 56% and 64%, respectively. With a median follow-up of 28 months (range, 7 to 53 months), the overall and disease-free survival rates were 40.5% (CI, 24% to 56%) and 32.3% (CI, 17% to 47%), respectively, although the median overall survival was 15 months.

There are anecdotal reports of relapsed AITL patients who have responded to immunosuppressive therapy, such as low-dose methotrexate/prednisone, as well as reports of responses to purine analogue treatment. Furthermore, cyclosporine has demonstrated activity in relapsed AITL patients in case reports. There are also anecdotal reports of responses to thalidomide plus steroid and to lenalidomide in AITL. In addition, long-term remissions have been seen with romidepsin treatment for AITL. Brentuximab vedotin has been effective in AITL patients overexpressing CD30 (approximately 20% of patients). Both autologous and allogeneic SCT have shown benefit in AITL, although the optimal timing remains open to debate.

Anaplastic Large Cell Lymphoma, T-/Null-Cell, Primary Systemic Type

ALCL, primary systemic type, is a CD30-positive T-cell lymphoma that accounts for approximately 2% to 3% of all NHLs. This disease mainly involves lymph nodes, although extranodal sites may be involved (not exclusively the skin; see subsection on ALCL, CD30+ cutaneous type). This disease may be divided, in part, on the basis of the expression of the tyrosine kinase ALK, created from a balanced chromosomal translocation t(2;5) and other less common translocations involving 2p23 (see Table 1). When heterogeneous patient populations are analyzed, the prevalence of ALK positivity in primary systemic ALCL cases is 50% to 60%. ALK-positive ALCL is typically diagnosed in men before age 35 (male to female ratio, 1.7:1), with frequent systemic symptoms and extranodal and advanced-stage disease. ALK-negative patients are usually older (median age, 61 years), with a male to female ratio of 1.5:1, with a similar high incidence of extranodal disease. In addition to the prognostic importance of ALK positivity, the IPI has been identified as an independent prognostic factor within the group of ALK-positive ALCL patients, with a reported 5-year overall survival of 94% vs 41% for IPI 0 or 1 and 2 to 4, respectively.

Therapy for pediatric ALCL is often based on prognostic risk factors, with treatment regimens modeled after high-grade B-cell NHL protocols. Following a brief cytoreductive prephase, short, intensified polyagent chemotherapy is administered, with the number of cycles dependent on the stage of disease. Therapy for adult ALCL, primary systemic type, has commonly included anthracycline-based regimens such as CHOP. Autologous hematopoietic SCT in first complete remission for ALK-negative ALCL has been advocated by some groups, although this approach warrants prospective validation. The immune antibody drug conjugate brentuximab vedotin, an anti-CD30 antibody linked to the antitubulin agent monomethyl auristatin E (MMAE), has shown remarkable clinical activity against this disease and is FDA-approved for this indication. In addition, the oral ALK and ROS1 inhibitor crizotinib (FDA-approved for treatment of some patients with non–small-cell lung cancer) has significant activity against ALK-positive ALCL.

Hepatosplenic T-Cell Lymphoma

Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon T-cell lymphoma that is seen mainly in young males (median age, 35) presenting with B symptoms, prominent hepatosplenomegaly, mild anemia, neutropenia, thrombocytopenia (commonly severe), significant peripheral blood lymphocytosis, and rare lymphadenopathy. It is associated with an aggressive clinical course (median survival, 12 to 14 months).

The tumor cells are usually negative for CD4 and CD8 (85%); positive for CD2, CD3, and CD7 (negative for CD5); and express CD56 in 70% to 80% of cases. TIA-1 is present in almost all cases, but commonly granzyme B and perforin are not present, an indication of a nonactivated cytotoxic T-cell phenotype. Cells usually express the γ/δ T-cell receptor (Vd1+/Vd2−/Vd3−) but are negative for EBV.

Historically, patients with HSTCL have been treated with CHOP-like regimens. Early autologous SCT has been favored by some investigators on the basis of anecdotal cases; however, if feasible, an allogeneic transplant may be more appropriate. A recent report described activity with the purine analogue pentostatin in relapsed HSTCL patients. Approximately 10% to 20% of HSTCL cases arise in immunocompromised patients, predominantly in the SOT setting.

Extranodal NK/T-Cell Lymphoma, Nasal Type

Extranodal NK/T-cell lymphoma, nasal-type, formerly known as angiocentric lymphoma, is rare in Western countries; it is more prevalent in Asia and Peru. The disease commonly presents in men at the median age of 50 years. This entity is associated with EBV and is typically characterized by extranodal presentation and localized stage I/II disease but with angiodestructive proliferation and an aggressive clinical course. These tumors have a predilection for the nasal cavity and paranasal sinuses (“nasal”), although the “nasal-type” designation encompasses other extranodal sites of NK/T-cell lymphomatous disease (skin, GI tract, testis, kidneys, upper respiratory tract, and rarely orbit/eyes).

Combined-modality therapy incorporating platinum-based chemotherapy (minimum of six cycles for patients with stage III or IV disease) and IFRT (minimum 50 Gy) is recommended for patients with extranodal NK/T-cell lymphoma, nasal type, although the benefit of the addition of chemotherapy to radiation therapy remains open to debate for limited-stage disease. A phase I/II study of concurrent chemoradiotherapy for untreated localized NK/T-cell lymphoma was conducted in Japan; it showed a 2-year overall survival of 78%, although confirmatory studies are warranted. Patients with systemic disease have poor long-term survival (5-year overall survival, 20% to 25%), with high locoregional (over 50%) and systemic (over 70%) failure rates. Asparaginase (Elspar) has been shown to have significant activity against this lymphoma, typically integrated with other agents, such as the regimen SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide).

Enteropathy-Associated T-Cell Lymphoma

Enteropathy-associated T-cell lymphoma (EATL; also known as intestinal T-cell lymphoma) is a rare T-cell lymphoma of intraepithelial lymphocytes that commonly presents with multiple circumferential jejunal ulcers in adults with a brief history of gluten-sensitive enteropathy. EATL accounts for less than 1% of NHLs, according to the International Lymphoma Study Group, and has been recognized to have a poor prognosis, with reported 5-year overall and disease-free survival rates of 20% and 3%, respectively. This finding is in part related to many patients presenting with a poor performance status and varied complications of locally advanced disease by the time a diagnosis of EATL has been confirmed.

EATL may present without an antecedent celiac history, but most patients have abdominal pain and weight loss. Evidence of celiac serologic markers such as positive antigliadin antibodies and/or HLA types such as DQA1*0501/DQB1*0201/DRB1*0304 may be present at diagnosis of EATL. Moreover, these genotypes may represent celiac patients at higher risk for development of EATL. Small-bowel perforation or obstruction, GI bleeding, and enterocolic fistulae are recognized complications of this disease. The immunophenotype consists of pan–T-cell antigens, usually CD8+, and the mucosal lymphoid antigen CD103 is often expressed.

Following diagnosis of EATL, doxorubicin-based combination chemotherapy should be considered for all patients, and aggressive nutritional support with parenteral or enteral feeding is critical in the care of these patients. Responding patients could potentially benefit from consolidation autologous SCT in first remission. Patients with known celiac disease should adhere to a gluten-free diet.

Adult T-Cell Leukemia/Lymphoma

The retrovirus HTLV-1 has been documented to be critical to the development of ATLL. HTLV-1 is known to cause diseases other than ATLL, including tropical spastic paraparesis/HTLV-1–associated myelopathy, infective dermatitis, and uveitis. In areas in Japan where HTLV-1 is endemic, approximately 10% to 35% of the population is infected with the virus. Among these carriers, the overall risk of ATLL is approximately 2.5% in patients who live to age 70. Of the Caribbean population, 2% to 6% are HTLV-1 carriers, whereas less than 1% of the population in lower-risk areas, such as the United States and Europe, are seropositive. HTLV-1 is transmitted through sexual intercourse, transfused blood products (products containing white blood cells, not fresh frozen plasma), shared needles, breast milk, and vertical transmission. Transfusion of HTLV-1–contaminated blood products results in seroconversion in approximately 30% to 50% of patients, at a median of 51 days.

The clinical features of 187 ATLL patients included a median age at onset of 55 years and lymphadenopathy (72%), skin lesions (53%), hepatomegaly (47%), splenomegaly (25%), and hypercalcemia (28%) present at diagnosis. The differential diagnosis between cutaneous ATLL and mycosis fungoides is often difficult. ATLL is separated into four subtypes divided by clinicopathologic features and prognosis: acute, lymphoma, chronic, and smoldering. Shimoyama and colleagues (Br J Haematol 1991) reported on the characteristics of 818 ATLL patients. Patients with acute-type ATLL present with hypercalcemia, leukemic manifestations, and tumor lesions and have the worst prognosis, with a median survival of approximately 6 months. Patients with lymphoma-type ATLL present with low circulating abnormal lymphocytes (< 1%) and nodal, liver, splenic, CNS, bone, and GI disease; the median survival is 10 months. Patients with chronic-type ATLL present with more than 5% abnormal circulating lymphocytes and have a median survival of 24 months, whereas the median survival of patients with smoldering-type ATLL has not yet been reached.

ATLL is an aggressive neoplasm with resistance to conventional chemotherapy, in part due to the viral protein Tax-mediated resistance to apoptosis and overexpression of p-glycoprotein (the product of the multidrug resistance-1 gene). Patients may initially respond to combination chemotherapy, but unfortunately, response durations are brief (5 to 7 months). El-Sabban and colleagues (Blood 2000) combined arsenic trioxide (Trisenox) with IFN-α, which induced cell-cycle arrest and apoptosis. Response rates of 70% to 90% with combination IFN-α and zidovudine therapy have been demonstrated in ATLL, with associated increased median survival rates compared with those of historic controls. The Japanese Clinical Oncology Group Study randomized patients with untreated aggressive ATLL to VCAP-AMP-VECP (vincristine, cyclophosphamide, Adriamycin [doxorubicin], prednisone-Adriamycin [doxorubicin], MCNU [ranimustine], prednisone-vindesine, etoposide, carboplatin, prednisone) chemotherapy or biweekly CHOP. They reported a higher complete remission rate and improved survival rates with VCAP-AMP-VECP, although treatment-related toxicity was high. Allogeneic SCT has been successfully employed in select patients.

Other agents with anecdotal activity in ATLL include irinotecan and the purine analogues (pentostatin and 2-chlorodeoxyadenosine, although pentostatin did not appear to improve outcomes when added to combination chemotherapy). Recently, the anti-CCR4 monoclonal antibody (mogamulizumab) was approved in Japan as monotherapy for ATLL, with a response rate of 50% and a median progression-free survival of 5.2 months.

Cutaneous T-Cell Lymphomas

CTCLs constitute a group of cutaneous NHLs with clonal expansion of T lymphocytes into the skin. Several entities are recognized by the combined European Organisation for Research and Treatment of Cancer (EORTC) and WHO classification, which is based on morphologic, histopathologic, and molecular features (Table 14). The frequency and disease-specific survival rates differ for each entity.

Mycosis Fungoides/Sézary Syndrome

Mycosis fungoides and its variants represent the most common type of CTCL, accounting for 50% of CTCLs, with a male predominance of approximately 2:1 and a predominance of African American patients of 1.6:1. It has a yearly incidence of 0.36 cases per 100,000 population that has remained constant over the past decade. Clinical and histologic diagnosis of mycosis fungoides has proved to be difficult, because in early stages, it may resemble other dermatoses, such as eczematous dermatitis, psoriasis, and parapsoriasis.

Clinically, mycosis fungoides is characterized by erythematous patches, evolving into plaques or tumors; however, the progress is variable. It is classified as an indolent lymphoma by the EORTC. The neoplastic cells have a mature CD3+, CD4+, CD45RO+, CD8Рmemory T-cell phenotype. S̩zary syndrome is the aggressive, leukemic, and erythrodermic form of CTCL, which is characterized by circulating atypical malignant T lymphocytes with cerebriform nuclei (S̩zary cells) and lymphadenopathy. Circulating S̩zary cells also have a mature memory T-cell phenotype with loss of CD7 and CD26. For staging purposes, the tumor node metastasis system is most commonly used (Table 15).

Investigative and recently approved options that have shown activity against mycosis fungoides/Sézary syndrome include the histone deacetylase inhibitors vorinostat (Zolinza, FDA-approved), romidepsin (Istodax, FDA-approved), and panobinostat; the novel antifolate pralatrexate (Folotyn, FDA-approved); the proteasome inhibitor bortezomib; and monoclonal antibodies targeting CD4 (zanolimumab), CCR4 (mogamulizumab), and CD30 (brentuximab vedotin) in select patients.

Treatment of early-stage disease

At present, CTCLs are regarded as incurable. In early CTCL, the cell-mediated immune response is usually normal. Therefore, the majority of these cases can be treated successfully with topical modalities. Early aggressive therapy does not improve the prognosis of patients with CTCL. The skin-targeted modalities include psoralen plus ultraviolet A (PUVA); narrow-band ultraviolet B; skin electron beam radiation therapy; spot radiation therapy; and topical preparations of steroids, retinoids, carmustine, or nitrogen mustard (Table 16). Radiation therapy prescriptions may be similar to those for other lymphomas or may be delivered at high doses in limited fractions. Excimer laser treatment can also be used for discrete lesions.

Treatment of advanced-stage disease

A limited number of patients progress to more aggressive and advanced disease with either cutaneous or extracutaneous tumor manifestations. Treatment goals in advanced stages should be to reduce the tumor burden, relieve symptoms, and potentially decrease the risk of transformation into aggressive lymphoma. Established treatment options are monochemotherapy (ie, gemcitabine, doxil) and polychemotherapy, including CVP, CHOP, and ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin) regimens; extracorporeal photopheresis; IFNs; retinoids and rexinoids (bexarotene [Targretin] capsules); histone deacetylase inhibitors (vorinostat and romidepsin); novel antifolates (pralatrexate); monoclonal antibodies (alemtuzumab); and recombinant toxins (denileukin diftitox). Combinations are frequently used (Table 16). Encouraging results with an anti-CD3 immunotoxin have been reported. Select patients with progressive and recalcitrant disease have been cured with an allogeneic SCT.

TABLE 14: The WHO–EORTC consensus classification for primary cutaneous lymphomas with relative frequency and 5-year survival

Primary Cutaneous CD30+ Lymphoproliferative Disorders

Primary cutaneous CD30+ lymphoproliferative disorders are the second most common group of CTCL, representing approximately 30% of CTCLs. This spectrum of diseases includes lymphomatoid papulosis, ALCL CD30+ cutaneous type, and borderline disorders. The distinction between these entities can be challenging and is often made on the basis of clinical behavior.

Lymphomatoid Papulosis

TABLE 15: Stage classification for mycosis fungoides and Sézary syndrome

Lymphomatoid papulosis is most commonly associated with mycosis fungoides, CD30+ large T-cell lymphoma, and Hodgkin lymphoma. Four histologic types have been identified, characterized as types A, B, C, and D. Types A and C consist of large lymphocytes resembling Reed-Sternberg cells. Type A cells are embedded in a dense inflammatory background, whereas type C cells form large sheets imitating CD30+ large T-cell lymphoma. Type B simulates classic features of mycosis fungoides, with epidermotropism and a dermal band-like infiltrate composed of small to medium-sized cells. Type D is CD8+. Lymphomatoid papulosis lesions occasionally exhibit clonal gene rearrangements.

Lymphomatoid papulosis represents a benign, chronic recurrent, self-healing, papulonodular, and papulonecrotic CD30+ skin eruption. However, a lymphoid malignancy may develop in 10% to 20% of patients, but the prognosis for patients with lymphomatoid papulosis is otherwise excellent, with a 5-year survival of 100%. There is no curative treatment available. Lymphomatoid papulosis is managed by observation, intralesional steroid injection, topical bexarotene, ultraviolet light therapy, or low-dose methotrexate. For select patients brentuximab vedotin is an option.

Anaplastic Large Cell Lymphoma, CD30+ Cutaneous Type

TABLE 16: Treatment options for cutaneous T-cell lymphoma by stage

Primary systemic CD30+ ALCL and primary cutaneous CD30+ ALCL represent identical morphologic entities, but they are clinically distinct diseases.

The neoplastic cells of primary cutaneous CD30+ ALCL are of the CD4+ helper T-cell phenotype with CD30 expression. It represents 9% of CTCLs and typically presents with solitary or localized nodules. This tumor has an excellent prognosis, as confirmed in several studies, in contrast to the transformation of mycosis lymphoma to a CD30– large cell variant. It shows histologic and immunophenotypic overlap with lymphomatoid papulosis. In most cases, tumor cells show anaplastic features, less commonly a pleomorphic or immunoblastic appearance. However, there is no difference in the prognosis and survival rate. Primary CD30+ ALCL rarely carries the t(2;5) translocation and is usually ALK-negative. These lesions may undergo spontaneous regression, as do the lesions of lymphomatoid papulosis. The mechanism of tumor regression remains unknown.

Local radiation therapy (30-40 Gy) or surgical excision is the preferred treatment, with systemic chemotherapy reserved for cases with large tumor burden and extracutaneous involvement. More recently, there has been reported efficacy of recombinant IFN-γ-1b (Actimmune) and combined treatment with bexarotene and IFN-α-2a (Roferon-A). Brentuximab vedotin treatment can provide sustained remissions. Durable responses have also been witnessed after treatment with liposomal doxorubicin (Doxil).

Subcutaneous Panniculitis-Like T-Cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) is a rare T-cell lymphoma that infiltrates the subcutaneous fat without dermal and epidermal involvement, causing erythematous to violaceous nodules and/or plaques. Approximately 20% of patients have an associated autoimmune disease, most commonly systemic lupus erythematosus. Systemic symptoms are frequent and include weight loss, fever, and fatigue. The disease may be complicated by the hemophagocytic syndrome. SCPTCL may be preceded by a benign-appearing panniculitis for years. The infiltrate is pleomorphic and associated with inflammation and necrosis. The T-cell phenotype is α/ß+ with CD4(+/−), CD8+, and CD56(−/+). Standard treatment has historically included CHOP-like chemotherapy. However, recent data suggest that patients can be controlled for long periods with local radiation treatment and/or steroids. Five-year survival rates exceed 80%.

Cutaneous γ/δ T-Cell Lymphoma

Cutaneous γ/δ T-cell lymphoma is a rare panniculitis presenting with disseminated (ulcerated) plaques, nodules, or tumors. Involvement of mucosal or extranodal sites is common. Systemic symptoms, including weight loss, fever, and fatigue, are almost always present. The hemophagocytic syndrome is often noted. The γ/δ+ T cells are characteristically CD2+, CD3+, CD4−, CD5−, CD7(−/+), CD8(−/+), and CD56+. Aggressive chemotherapy is indicated, with consideration of autologous or allogeneic SCT incorporated into the initial treatment schema. The median survival is less than 2 years.

Pleomorphic T-Cell Lymphomas With Small/Medium Cells

The small/medium pleomorphic CTCL type appears clinically with single erythematous to violaceous nodules or tumors and accounts for less than 3% of CTCL cases. Most advanced cases have an unfavorable prognosis, with a median survival of 24 months or less; however, the CD3+, CD4+, CD8−, CD30− subtype with limited lesions often of the face and upper trunk has a favorable prognosis with a 5-year survival rate exceeding 90%.

The optimal therapy for pleomorphic T-cell lymphomas with small/medium cells has not been defined. Localized lesions have been treated with radiation therapy or surgical excision. Patients with generalized skin disease or progression have been treated effectively with systemic treatments, including multiagent chemotherapy, retinoids, IFNs, and monoclonal antibodies.

Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma is currently a provisional entity in the WHO classification of mature T-cell and NK-cell neoplasms. It is a rare disease accounting for less than 1% of CTCL. Most patients are adults and present with generalized papules, nodules, hyperkeratotic patches, and/or plaques. Central ulceration and necrosis is common. Dissemination to other visceral sites, including lung, testis, oral mucosa, and the CNS, is common; the lymph nodes are usually spared. The histologic appearance, although quite variable, includes proliferation of epidermotropic CD8+ cytotoxic malignant clonal T-cells. Invasion and destruction of adnexal skin structures and angiocentricity are common.

An aggressive clinical course is typical with a median survival of less than 3 years. Combination chemotherapy rarely provides a sustained remission. Antifolates can be effective in some patients. Allogeneic SCT should be a consideration in medically fit patients.

Cutaneous B-Cell Lymphomas

Primary cutaneous B-cell lymphomas (CBCLs) are rare entities. They constitute up to 25% of all cutaneous lymphomas. However, the incidence of CBCLs has been underestimated because of the absence of immunologic and molecular markers. In addition, their terminology and classification remain controversial, with, until recently, separate and distinct terminology promoted by WHO and EORTC. Primary CBCLs are distinct from nodal lymphomas, and the majority of them have an excellent prognosis. Several types are recognized, with the most common types being follicular center lymphoma and marginal zone lymphoma.

Primary cutaneous follicular center lymphoma

Primary cutaneous follicular center lymphoma (PCFCL) is defined as a proliferation of centrocytes (small to large cleaved cells) and centroblasts (large round cells with prominent nuclei) that show a nodular or diffuse infiltrate in the majority of cases and presenting only rarely a true follicular pattern. PCFCL is the most common subtype of CBCLs, accounting for 40% of CBCLs. PCFCL shows a predilection for the head, neck, and trunk in elderly patients, with a median age of 60 years and a male predominance of approximately 1.5:1. The clinical course is usually indolent, with an excellent overall survival of up to 97%. However, relapses occur frequently. The large round cell morphology might be associated with a higher rate of disease progression and poorer prognosis.

Small centrocytes predominate in low-grade PCFCL, whereas an increased number of large cells occurs in high-grade PCFCL; however, lesions with pure high-grade disease may behave indolently and should not by themselves drive the treatment administered. In contrast to their nodal counterpart, BCL2 is usually not expressed in neoplastic cells, and the t(14;18) translocation is rarely detected. More recently, low rates of BCL2 expression have been reported. In addition to CD10+ and BCL6+ expression, PCFCL also has an aberrant expression of CD45 RA and CD43 and thus provides a helpful clue to distinguish it from pseudolymphomas. Radiation therapy (24-30 Gy) is often the preferred therapy for solitary or localized group lesions. Surgical excision can be considered for small lesions. Chemotherapy, although effective, rarely results in cure. Rituximab has proved to be effective for palliation. Observation is a reasonable alternative in many instances.

Primary cutaneous marginal zone lymphoma

Primary cutaneous marginal zone lymphoma (PCMZL) is a recently recognized low-grade lymphoma and represents the second most common subtype of CBCLs. It predominantly occurs on the upper and lower extremities. The median age at presentation is 55 years, and females are affected more often than males. The reported survival rates are 97% to 100%, although relapses commonly occur. Histologically, PCMZL has features of MALT lymphomas and shows a nodular or diffuse dermal infiltrate with a heterogeneous cellular infiltrate of small lymphocytes, lymphoplasmacytoid cells, plasma cells, intranuclear inclusions (Dutcher bodies), and reactive germinal centers that may be infiltrated by neoplastic cells. Diagnosis can be difficult, because of the variable composition of the infiltrate that may be interpreted as a reactive process or as PCFCL. In contrast to PCFCL, marginal zone lymphoma is negative for BCL6 and CD10. In 50% of cases, CD43 is highly expressed. Large-cell transformation and a head and neck presentation may be associated with a worse prognosis. Therapeutic alternatives are similar to those described for PCFCL.

Primary cutaneous diffuse large B-cell lymphoma, leg type

EORTC and the International Society for Cutaneous Lymphomas consensus recommendations for the management of CBCLs have been published by Senff and coworkers. Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT) forms a separate category in the WHO-EORTC classification, as a more aggressive type seen in elderly patients, with a median age of 76 years at diagnosis and a female predominance of 7:2. Most cases have a follicle center cell origin, and histologic evaluation shows a diffuse dermal infiltrate with predominance in large B cells with multilobulated nuclei, consisting of centroblasts and immunoblasts, with the presence of small, cleaved cells and a minor admixed infiltrate component. Eosinophilic intranuclear (Dutcher body) or intracytoplasmic (Russell body) inclusions of immunoglobulin are common. Unlike PCFCL, PCLBCL, LT consistently expresses BCL2, although it is not associated with the t(14;18) translocation.

The prognosis is less favorable for PCLBCL, LT than for other CBCLs, with a 5-year survival rate of 50% to 60%. Prognostic factors identified with a poor outcome include the predominance of round cells (centroblasts/immunoblasts) over cleaved cells (centrocytes) in the tumor infiltrate, MUM1 expression, and multiple lesions at presentation. The use of an IPI-based model is required to investigate whether PCLBCL, LT is associated with a poorer prognosis. These lymphomas should be treated as systemic DLBCLs with anthracycline-based chemotherapy. In patients who present with a single, small skin tumor, radiotherapy is a consideration. Rituximab has also been incorporated into combination regimens.

Intravascular large B-cell lymphoma

WHO and EORTC have proposed intravascular large B-cell lymphoma (IVLBCL), or angiotropic B-cell lymphoma, as a provisional entity. This subtype is rare and corresponds to the proliferation of malignant lymphocytes within lumina of small vessels, involving most frequently the skin and CNS. It was previously considered a vascular tumor and referred to as malignant angioendotheliomatosis. Although the majority of cases are of B-cell origin, a few cases of T-cell lineage have been reported. The reason for intravascular localization is not clear, but association with an unknown surface receptor or dysfunction of lymphocyte-endothelial interaction affecting adhesion molecules has been suspected.

IVLBCL is clinically characterized by tender erythematous, purpuric, indurated patches and plaques located on the trunk and thighs, where it can resemble panniculitis. Cases of generalized telangiectasia over normal skin have been reported. Cytomorphology reveals intravascular occlusion of small vessels, filled with large atypical centroblast-like B lymphocytes. IHC shows CD19, CD20, CD45, and CD79a expression. Genotypic analysis has demonstrated clonality, although it may not be positive in every case. Generally, the prognosis of this aggressive type of lymphoma is poor despite the use of combination chemotherapy, because of the initial or secondary CNS involvement. However, rituximab appears to have had a significantly favorable impact on the outcome of patients with IVLBCL.

CD4+/CD56+ Hematodermic Neoplasm

The CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma) commonly presents in the skin, with nodular and extracutaneous systemic involvement. This rare disorder appears to be derived from a plasmacytoid dendritic cell precursor. T-cell receptor genes are in germline configuration. This entity causes a dismal prognosis (median survival, 14 months) despite intensive chemotherapy. For this reason, this disease is often treated as an acute leukemia. The novel IL-3 (CD123) receptor-directed recombinant diphtheria toxin protein, SL-401, has received orphan drug designation from the FDA.

Plasmacytoma

Primary cutaneous involvement of plasmacytoma is uncommon and generally develops as a consequence of direct spread from an underlying multiple myeloma. It represents 4% of extramedullary plasmacytomas and affects predominantly elderly men, with a median age of 60 years at diagnosis. It is characterized by a monoclonal proliferation of mature plasma cells. Cutaneous plasmacytomas are potentially curable, with a 5-year survival rate of more than 90%. However, the presentation of multiple lesions is an important adverse prognostic factor. Histopathology shows a dense monomorphous dermal infiltrate of plasma cells with a varying degree of maturation and atypia, admixed with few lymphocytes and histiocytes. Neoplastic plasma cells express clonal immunoglobulin, CD38, and CD79a but are negative for CD20. Rarely, amyloid deposition within the tumor is demonstrated, which is more common in secondary cutaneous involvement of plasmacytoma. A recent organized workshop on plasma cell dyscrasias questioned whether these cases are true cutaneous plasmacytomas, represent reactive B-cell infiltrates associated with an infectious etiology, or represent a variant of marginal zone lymphoma with a predominant population of plasma cells. Diagnosis may rely on demonstration of monoclonality by restriction of immunoglobulin light-chain expression. Excision or radiation treatment is most commonly used.

HIV-Related Lymphomas

Most lymphomas seen in patients who have HIV infection are of an aggressive histology and advanced stage at presentation. Extranodal disease is common, with unusual sites of presentation, including the GI tract, CNS, and multiple soft tissue masses. Some patients present with primary CNS lymphoma. Poor-risk factors include a high LDH level, large tumor bulk, extranodal disease, and low CD4 cell counts (< 100/µL). Because of their increased risk of opportunistic infections and impaired hematologic reserve, many patients with HIV-related lymphomas historically have been unable to tolerate aggressive chemotherapy regimens. Current antiviral medications have allowed for the use of more traditional regimens, including R-CHOP and EPOCH-R, with results comparable to those of other NHL patients with similar histologies and presentations. CNS prophylaxis with intrathecal chemotherapy is necessary to prevent meningeal dissemination. (For a more detailed discussion of HIV-related NHL, see the “AIDS-Related Malignancies” chapter.)

Posttransplant Lymphoma

Posttransplant lymphoproliferative disorders (PTLDs) remain a morbid complication associated with SOT. The incidence varies from 1% to 2% in renal transplant recipients and up to 12% to 14% in heart or multi-organ transplant recipients; the latter patient groups require more potent immunosuppressive therapy.

The pathologic spectrum of PTLD is heterogeneous, comprising a spectrum ranging from hyperplastic-appearing lesions to frank aggressive lymphoma. The most frequent subtype seen is monomorphic, of which the most common histology is akin to DLBCL. PTLDs are fully depicted in the updated WHO classification (see Table 4). Historically, PTLDs were reported to occur at a median of 6 months from SOT, although recent data suggest this interval is likely longer (ie, median 40 to 50 months). Early PTLD cases (ie, < 12 months after SOT) more often express EBV, whereas late-onset cases are typically EBV-negative.

Recent evidence suggests improved outcomes for PTLD in the modern era. Treatment initially involves the reduction of immunosuppression (usually by at least 50%), especially for early EBV-positive cases. EBV-negative PTLD will respond to immunosuppression reduction, but less frequently than EBV-positive cases. In addition, the status of the transplanted organ will in part dictate the amount of immunosuppression safely allowable to avoid organ rejection. The exact role of rituximab in B-cell PTLD continues to be defined. Single-agent rituximab was evaluated in two phase II studies of patients in whom reduction of immunosuppression failed, with reported overall response rates of 42% and 73% and modest survival rates. A retrospective series using frontline rituximab-based therapy, in conjunction with reduced immunosuppression, was associated with significantly improved survival compared with prior reports. In addition, a recent prospective PTLD clinical trial using sequential rituximab followed by CHOP therapy showed good outcomes. Final results of the latter trial, which studied a response-adapted therapeutic strategy with frontline single-agent rituximab, are eagerly awaited.

The decision of initially treating with rituximab alone vs concurrent or sequential rituximab with chemotherapy (eg, R-CHOP) is often determined on a patient-by-patient basis. Factors in small studies associated with lower response to rituximab in PTLD include EBV-negative disease and elevated LDH levels. In addition, chemotherapy may be needed as initial therapy for patients who have a large tumor burden warranting rapid response of disease. Of note, during chemotherapy, immunosuppressant medication doses should be either significantly reduced or carefully stopped completely, in part to avoid infectious complications. Carefully selected patients with relapsed/refractory monomorphic PTLD are able to receive high-dose chemotherapy followed by autologous SCT, with long-term survival noted in some reports.

Anecdotal reports have described the activity of thymidine kinase inhibitor antiviral therapies such as ganciclovir and acyclovir to prevent and/or treat PTLD, although the data are not convincing. This finding is not surprising, because EBV survives as an episome outside the lymphocyte genome, and these drugs do not eradicate latently infected B cells. However, one group has shown that arginine butyrate was able to induce EBV tyrosine kinase activity in EBV-immortalized B cells and convert patient-derived latently infected B-cell lymphoma tumor cells that were resistant to ganciclovir to a sensitive phenotype. A phase I/II study with encouraging clinical results was reported. In hematopoietic SCT-related PTLD, EBV-specific cytotoxic T lymphocytes (CTLs) have been used with encouraging results. In addition, the use of adoptive immunotherapy with EBV-specific CTLs continues to be explored in PTLD (Sidebar).

Sidebar: Recent studies from the Baylor group have shown the utility of T cells primed against EBV and other viruses in patients with EBV-related immune deficiency associated lymphomas. In novel studies, the Baylor group has used genetically modified expanded CTLs that were enriched for specificity against type II latency latent membrane protein (LMP) antigens. When these were infused into 50 patients with EBV-associated lymphoma, there were no infusion-related toxicities. Furthermore, 28 of 29 high-risk or multiply-relapsed patients receiving LMP-CTLs as adjuvant therapy remained in remission a median of 3.1 years after infusion. Of 21 patients who had active disease at the time of infusion, 13 had responses, including 11 complete responses. Duration of the responses in patients with active disease were not described. It is clear from these and similar studies that this approach to EBV-mediated and other virus-mediated lymphomas may be addressed by T-cell–mediated, immunotherapy-based approaches (Bollard CM et al: J Clin Oncol 32:798-808, 2014; Papadopoulou A et al: Science Transl Med 6:242ra83, 2014; Leen AM et al: Immunol Rev 258:12-29, 2014).

Primary CNS Lymphoma

Primary CNS lymphoma is a rare form of NHL, arising within and confined to the CNS. Histologically, primary CNS lymphomas are indistinguishable from systemic NHLs. A stereotactic needle biopsy is the procedure of choice for diagnosis. Resection does not appear to improve survival. More than 40% of patients have evidence of leptomeningeal dissemination, and 15% have ocular disease at presentation. Thus, examination of the eyes for lymphoma (slit lamp) at diagnosis is important, as is MRI of the entire neurospinal axis, to rule out multifocal disease.

The two most important prognostic factors in primary CNS lymphoma are age (> 50 years) and poor performance status (Karnofsky performance score < 70). Retrospective studies have documented that treatment of primary CNS lymphoma with whole-brain radiotherapy (WBRT) alone (with or without corticosteroids) results in a median survival of 10 to 15 months, with a 5-year survival of 3% to 4%. Current standard therapy for newly diagnosed primary CNS lymphoma is systemic chemotherapy, including high-dose intravenous methotrexate-based therapy (at least 2,500 to 3,500 mg/m2 per cycle) commonly combined with agents that penetrate the CNS (vincristine, procarbazine, and high-dose cytarabine). This regimen results in median survival rates of 50 to 60 months. The most important component in the treatment of primary CNS lymphoma is the use of high-dose methotrexate therapy (at least 2,000 mg/m2 and up to doses of 8,000 mg/m2). WBRT had been considered a standard component following chemotherapy; however, long-term neurotoxicity remains a major concern, especially for patients older than 60 years.

A study by Morris and colleagues reported encouraging results for primary CNS lymphoma patients who achieved complete remission following five to seven cycles of high-dose methotrexate-based chemoimmunotherapy and subsequently received reduced-dose WBRT (23.4 Gy) compared with the standard WBRT of 45 Gy. A German study randomized 551 patients, of whom 318 were treated per protocol, to high-dose methotrexate and ifosfamide with or without WBRT. The non-inferiority hypothesis was not proved statistically; however, the median overall survival in the WBRT population was 32.4 months vs 37.1 months without WBRT. In addition, the Alliance US Cooperative Group recently reported outcomes using a non–radiation-based therapeutic regimen.

Long-term survival data are also available using autologous or allogeneic SCT for relapsed/refractory primary CNS lymphoma, although an important prognostic factor is control of CNS disease immediately before transplant. Further, most transplant conditioning regimens for CNS lymphoma have incorporated thiotepa-based therapy (eg, busulfan, cyclophosphamide, and thiotepa).

Sidebar: Rubenstein and colleagues used a treatment regimen consisting of methotrexate, temozolomide, and rituximab induction followed by high-dose consolidation with etoposide plus cytarabine for patients with untreated primary CNS lymphoma. With median follow-up of nearly 5 years, the 2-year progression-free survival was 57%, which appears comparable with radiation-related regimens. In addition, older patients appeared to fare as well as younger patients, while high tumor BCL6 expression correlated with inferior survival (Rubenstein JL et al: J Clin Oncol 31:3061-3068, 2013).

Tumor Lysis Syndrome

Tumor lysis syndrome is a common complication after treatment of high-grade, bulky NHLs (because of their exquisite sensitivity to therapy and high proliferative capacity). The syndrome is characterized by renal failure, hyperkalemia, hyperphosphatemia, and hypocalcemia. Measures to prevent this complication include aggressive hydration; allopurinol; alkalinization of the urine; and frequent monitoring of electrolytes, uric acid, and creatinine. Dialysis is sometimes required. Rasburicase, a recombinant urate-oxidase enzyme, is now available for the prevention and treatment of hyperuricemia. (For a more comprehensive discussion of the tumor lysis syndrome, see the “Oncologic Emergencies and Paraneoplastic Syndromes” chapter.)

Lymphoma During Pregnancy

Lymphoma is one of the most common cancers diagnosed during pregnancy, occurring in approximately 1 in every 5,000 gestations. Evens and colleagues recently reported outcomes from a retrospective analysis of 50 patients with NHL that occurred during pregnancy. Median age at diagnosis for B-cell NHL was 29.5 years vs 34 years for T-cell lymphoma (P = .09). The most common NHL diagnosis was DLBCL, which accounted for 56% of all NHLs and 73% of B-cell NHLs. Fifty-four percent of NHL patients had advanced-stage disease, although functional imaging was not performed in any patient. Interestingly, extranodal disease was still frequently identified, with 26% of patients having more than one extranodal site, with several atypical sites seen (eg, vaginal, breast). Diagnosis of lymphoma occurred at a median of 23 weeks, with all but one patient having untreated disease. Pregnancy was terminated in six NHL patients; among the remaining patients, 15 (32%) had therapy deferred until postpartum. In the latter patients, a diagnosis was made at a median of 30 weeks’ gestation compared with 22 weeks’ gestation for patients who received antenatal therapy (P < .001).

Antenatal treatment was started at a median of 25 weeks’ gestation (range, 13 to 37 weeks). Four of the five NHL patients who received antenatal radiotherapy had supra-diaphragmatic stage I-II disease, while most patients who received antenatal therapy were treated with conventional non-antimetabolite chemotherapy regimens (eg, CHOP). The overall response rate for NHL patients who received antenatal therapy was 71% (complete remission 50%). The most common preterm complication was induction of labor (33%), while gestation went to full term in 56% of patients, with delivery occurring at a median of 37 weeks. Interestingly, there were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred vs antenatal therapy. At a median follow-up of 41 months, 3-year progression-free survival and overall survival for NHL patients were 53% and 82%, respectively. On univariate analysis for NHL, radiotherapy predicted inferior progression-free survival, and increased LDH levels and poor ECOG performance status portended worse overall survival. It is highly advocated that patients be managed concurrently with high-risk maternal-fetal medical consultation.

Follow-Up of Long-Term Survivors

Relapse

Among patients with aggressive lymphoma subtypes, most recurrences are seen within the first 2 years after the completion of therapy, although later relapses may occur. Physical examination and laboratory testing at 2- to 3-month intervals and follow-up CT scans (with or without PET scan) at 6-month intervals for the first 2 years following diagnosis are recommended. However, it is recognized that on relapse of disease, the patient usually presents with symptoms rather than the relapse being diagnosed purely on the basis of surveillance scans or routine clinic visits. Early detection of recurrent disease is important because these patients may be candidates for potentially curative high-dose therapy and SCT. Patients with advanced low-grade NHL are at a constant risk of relapse, and late recurrence of disease may be seen, sometimes after more than a decade-old remission.

Treatment Complications

There has been a more selective use of irradiation as part of the initial therapy for NHL; therefore, the risk of certain radiation-induced complications has been reduced or eliminated in patients with more recently diagnosed NHL. Nevertheless, total-body irradiation may be used as a component of myeloablative conditioning regimens. Also, transplant recipients are at increased risk for secondary myelodysplasia and acute myeloid leukemia, regardless of whether they received a radiation-containing conditioning regimen. All individual chemotherapy agents have their own potential long-term morbidity, such as late cardiovascular disease with anthracycline therapy.

Secondary Malignancies

Long-term survivors are at increased risk for second cancers. In a survey of 6,171 patients with NHL who survived 2 or more years, nearly 1,000 patients lived 15 or more years after diagnosis. Second cancers were reported in 541 patients, with significant excesses seen for all solid tumors; acute myeloid leukemia; melanoma; Hodgkin lymphoma; and cancers of the lungs, brain, kidneys, and bladder. The actuarial risk of developing a second malignancy at 3 to 20 years after diagnosis of NHL was 21%, compared with a population-expected cumulative risk of 15%.

Long-term survivors need continued follow-up for possible treatment-related complications. Some of these toxicities may still be unknown. Careful documentation of late complications will be important in the design of future treatment strategies aimed at preserving or improving response rates and the duration of remission while reducing toxicity.

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