Lymphomas

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Copyright 2010 American Society of Hematology. All rights reserved.
Chapter 18 Lymphomas Kerry J. Savage and Stephanie A. Gregory
Go to original online chapter: http://ash-sap.hematologylibrary.org/cgi/content/full/2010/1/511
This chapter is from the ASH Self-Assessment Program, available at www.ash-sap.org. This third edition includes a textbook divided into 18 chapters, each dedicated to a specific area of hematology. Also included is 1 of 2 test modules. To decide which test module is right for you or to learn more, go to http://ash-sap.hematologylibrary.org/misc/whichSAP.dtl.
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CHAPTER
18
Lymphomas
Kerry J. Savage and Stephanie A. Gregory
Overview of lymphocyte development, 511 Non-Hodgkin lymphomas, 516 Immunodeciency-associated lymphoproliferative disorders, 539 Hodgkin lymphoma, 541 Acknowledgment, 547 Bibliography, 548
Overview of lymphocyte development

Lymphocytes develop from a common lymphoid progenitor cell. B cells mature primarily in the bone marrow, whereas T cells mature in the thymus. Although the process and signals of maturation differ between the 2 cell types, they rely on similar genetic events to generate specic antibodies or cell surface receptors. These gene rearrangements are critical for the development of a broad immune repertoire and also provide molecular markers of clonality that can be used to diagnose lymphoid malignancies. B-cell development B-cell maturation consists of early (antigen-independent) and late (antigen-dependent) stages. Early development is initiated by the rearrangement of genes for the heavy and light chains of antibodies, a process referred to as V/(D)/J recombination. The earliest B-precursor cell shows rearrangement of the immunoglobulin heavy chain, which is then followed by light chain rearrangement. The light chain genes rearrange rst; if neither locus is productively rearranged, then the gene loci undergo rearrangement. Once a successful light chain rearrangement occurs, the cell will express the complete
Conict-of-interest disclosure: Dr. Savage: honoraria: Roche, Eli Lilly. Dr. Gregory: consultancy: Amgen, Genentech; research funding: Amgen, Boehringer Ingelheim, Celgene, CTI, Genentech, GenMab, GlaxoSmithKline, Gloucester Pharmaceuticals, Millennium, NCIC CTG, Rigel Pharmaceuticals; speakers bureau: Genentech, GlaxoSmithKline, Millennium. Off-label drug use: Dr. Savage and Dr. Gregory: rituximab maintenance after rituximab chemotherapy in lymphoma; radioimmunotherapy for consolidation therapy after chemotherapy for initial treatment of lymphoma; bortezomib and combinations in Waldenstrm macroglobulinemia, rituximab in hairy cell leukemia, R-CHOP in localized DLBCL, thalidomide in mantle cell lymphoma.
immunoglobulin molecule on its surface, which identies it as a mature B cell. Mature B cells will typically express either immunoglobulin M (IgM) or immunoglobulin D (IgD) on their surface, and this surface expression is critical to cell survival. Further, the combination of the VDJ gene sequences is unique for each immunoglobulin molecule variable region and, hence, each B cell and is referred to as the idiotype. Cell surface markers are also used to dene the early stages of B-cell development. CD10 (CALLA, the common acute lymphoblastic leukemia antigen) and CD19 are expressed on immature B cells (pro-B and B precursor) that have begun heavy chain rearrangement. Terminal deoxynucleotidyl transferase (TdT), a DNA polymerase important for nucleotide chain elongation during gene rearrangement, is also expressed at this stage. CD20 is then expressed as cells rearrange light chains and express surface immunoglobulin, and the expression of CD10 and TdT is lost. The mature but antigen-naive B cell leaves the bone marrow to circulate and populate lymphoid organs such as lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT). The late, or antigen-dependent, stages of B-lymphocyte development begin when a naive B cell recognizes an antigen with its membrane-bound antibody. These B cells collect in germinal centers of the various lymphoid organs and begin to divide and undergo several types of genetic modication. Somatic hypermutation is a process by which cells introduce mutations into the variable region (V) genes. These mutations result in antibodies that may have a higher or lower afnity for the antigen. Those that produce a higher afnity antibody will persist and become either plasma cells or memory B cells, whereas those that fail to produce functional antibody at this stage will undergo apoptosis. Class switching involves changing the heavy chain that is expressed to produce other antibody classes: immunoglobulin G (IgG), immunoglobulin A (IgA), or immunoglobulin E (IgE).
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512 | Lymphomas
Although this switch does not alter antibody afnity, the change in class of antibody will alter its effector function and thereby affect the immune response. T-cell development T-cell maturation occurs in the thymus, where T-cell precursor thymic stroma interactions guide the maturation and selection of mature T cells. The differentiation steps of the T lymphocyte are in many ways parallel to those of B lymphocytes. The 4 T-cell receptor (TCR) genes, , , , and , undergo rearrangement analogous to that seen in the immunoglobulin gene locus. These proteins form heterodimeric receptors in mature lymphocytes, and any given T cell expresses either an - or a - TCR on its surface, but not both. Once a TCR is expressed on the surface of the developing thymocyte, the cell undergoes both positive and negative selection. Positive selection requires the TCR to recognize a self-peptide major histocompatibility complex (MHC) molecule, and negative selection then ensures that the TCR MHC binding afnity is not high, which could indicate an autoreactive clone. Cells that survive positive and negative selection then exit the thymus as mature T cells. In addition to the TCR, other surface molecules expressed on mature T cells include the CD3, CD4, and CD8 proteins. The TCR is expressed in association with the CD3 antigen, expression of which is considered to be the denitive marker of T-cell identity. Coreceptors with the TCRCD3 complex are CD4 and CD8, which identify helper and cytotoxic/ suppressor subtypes, respectively. Most mature T cells will express either CD4 or CD8, although there are occasional cells that express both. In addition, virtually all T cells express the pan-T-cell marker CD5; this same marker is expressed on a subset of normal and malignant B cells such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) (see the Non-Hodgkin lymphomas section). Absence of CD5 expression on circulating lymphocytes with some characteristics of T cells is a marker of natural killer (NK) cells; however, it can also be an important marker for lymphoproliferation because many neoplasms of phenotypically mature T cells lack CD5 expression. Biology of lymphomas The transforming events in lymphoproliferative disorders are best understood for B-cell processes. Analysis of V genes from a variety of B-cell neoplasms reveals evidence of somatic mutation, which indicates that they arise from germinal center or postgerminal center B cells. This suggests that the germinal center is a site of initiation of the transforming event, as cells undergo a number of DNA-modifying events including class switching and somatic hypermutation. Failure of these processes may result in inappropriate translocations
Table 18-1 Risk factors in the development of non-Hodgkin lymphoma. Viral Bacterial Impaired/altered immunity Congenital Acquired EBV, HTLV-1, HHV-8, hepatitis C Helicobacter pylori Ataxia-telangiectasia Wiskott-Aldrich syndrome Severe combined immunodeciency AIDS (HIV infection) Organ or stem cell transplantation Aging Autoimmune disease Herbicides Pesticides
Environmental or occupational
AIDS acquired immunodeciency syndrome; EBV Epstein-Barr virus; HHV-8 human herpesvirus 8; HIV human immunodeciency virus; HTLV-1 human T-cell lymphotropic virus 1.
(oncogene to immunoglobulin switch region) or point mutations in oncogenes, resulting in unregulated oncogene activation. Similar errors in DNA rearrangement can occur during V/(D)/J recombination, resulting in precursor B- or T-cell malignancies. Several viral infections are also associated with the development of lymphoproliferative disorders, including Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8) (Table 18-1). Diagnostic testing in lymphoproliferative disorders In general, there are no surface markers that are diagnostic of malignancy in lymphocytes. Several methods are used to document a lymphoid malignancy including morphology (lymph node, peripheral blood, or bone marrow), immunophenotyping, molecular genetics, and cytogenetics. Morphology Many lymphoproliferative malignancies are diagnosed by characteristic morphology of a lymph node or other biopsy. Examination of patterns of growth, degree of cytologic atypia, degree and type of differentiation, and the presence of reactive components are important for diagnosis. Fine needle aspiration can be used to identify an abnormal population of cells but furnishes none of the structural information provided by a core or excisional biopsy. For that reason, an excisional biopsy is recommended for the initial diagnosis of a suspected lymphoproliferative disorder. Immunophenotyping Diagnosis by immunophenotyping is based on nding increased expression of a certain marker (or markers) that is usually present only on a small percentage of normal cells. For B-cell malignancies, clonality can be identied by light
Overview of lymphocyte development | 513
Table 18-2 Phenotypic markers and chromosomal translocations in non-Hodgkin lymphomas. NHL CLL/SLL Follicular Mantle cell Marginal zone/ extranodal marginal zone lymphoma Lymphoplasmacytic lymphoma Hairy cell leukemia DLBCL sIg Weak CD5 CD10 CD20 Weak Other CD23, FMC Cyclin D1 Cytogenetics No diagnostic abnormalities* t(14;18) t(11;14) t(11;18) Oncogene BCL2 Cyclin D1 AP12-MALT Function Antiapoptosis Cell cycle regulator Resistance to Helicobacter pylori treatment Antiapoptosis Transcription factor Transcription factor Transcription factor Tyrosine kinase
CD23, FMC
Rare
CD25/, CD38/ CD11c, CD25, CD103
Weak
t(9;14) t(14;18), t(3;14), t(3;v) BCL2 t(8;14), t(2;8), t(2;22) BCL6 Rare CMYC t(8;14), t(2;8), t(2;22) t(2;5) CMYC ALK
Burkitt lymphoma ALCL, ALK-positive
TdT CD2, CD3/, EMA
*See chapter on CLL/SLL (Chapter 19) for prognostic cytogenetic abnormalities. ALCL anaplastic large-cell lymphoma; CLL chronic lymphocytic leukemia; DLBCL diffuse large B-cell lymphoma; MALT mucosaassociated lymphoid tissue; sIg surface immunoglobulin; SLL small lymphocytic lymphoma; TdT terminal deoxynucleotidyl transferase.
chain restriction of the surface immunoglobulin. B cells normally express and light chains in a ratio of 2:1. A clonal expansion can be identied by a marked predominance of either - or -expressing B cells. This would not be expected in a reactive process. Some pan-B-cell surface markers are frequently coexpressed, such as CD19, CD20, and CD22. Others, including CD5, CD10, and CD23, are helpful in the differential diagnosis of B-cell neoplasms, such as differentiating CLL/small lymphocytic lymphoma (SLL) (CD5, CD19, CD23) from follicular lymphoma (CD5, CD10, CD19) or MCL (CD5, CD19, CD23) (Table 18-2). The immunophenotyping of T-cell neoplasms is less conclusive than for B-cell disorders because T cells lack the equivalent of light chain restriction. Several ndings can be suggestive of neoplasia, including expression of CD4 or CD8 on the majority of the T cells, lack of expression of CD4/CD8 or a pan-T-cell marker on the majority of T cells, or coexpression of CD4 and CD8 on the majority of T cells. Often, however, molecular techniques to look at TCR gene rearrangements are necessary to differentiate reactive from clonal T-cell processes. Molecular genetics/cytogenetics Molecular genetic techniques can be helpful in assessing clonality when morphology and immunophenotyping are
inconclusive. These involve isolating the DNA from a sample and subjecting it to Southern blot analysis or polymerase chain reaction (PCR) to detect rearrangements of immunoglobulin or TCR genes. The demonstration of a dominant rearrangement of the immunoglobulin or TCR genes is indicative of a clonal process. PCR testing has several advantages over Southern analysis, including increased sensitivity, smaller amounts of clinical sample with which to run the assay, and decreased time to perform the test. Chromosomal translocations are common in lymphoproliferative disorders and can therefore provide useful markers of malignancy. Many oncogene translocations may contribute to the transformation process or cellular proliferation. The nding of particular translocations can help conrm a diagnosis [eg, the t(11;14) in MCL] and can be used for monitoring of disease status following treatment (Table 18-2). The use of microarray technology has also been used to dene the gene expression prole of various lymphoid malignancies and to compare them to normal lymphoid populations. This has been successfully applied to a number of B-cell lymphomas, including diffuse large B-cell lymphoma, follicular lymphoma, CLL, and MCL to identify expression patterns that correlate with patient outcome. It has also identied novel genes that may be important for malignant transformation, which could increase our
514 | Lymphomas
understanding of lymphomagenesis and potentially elucidate novel therapeutic targets. Classication of lymphomas The classication of lymphoproliferative disorders has evolved as a result of an increased understanding of the biology of these diseases. The current classication system used is the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, which was updated in 2008 (Tables 18-3 and 18-4). This classication recognizes B-cell and T-cell/NK-cell neoplasms and Hodgkin lymphoma (HL). The B- and T-cell neoplasms are separated into precursor (lymphoblastic) neoplasms and mature B- or T-cell neoplasms. The precursor neoplasms are reviewed in Chapter 17, and B-cell and T-cell prolymphocytic leukemia are discussed in Chapter 19. There have been a number of updates and disease renements in both the B-cell lymphoma and T-cell lymphoma sections of the World Health Organization (WHO) classication. Changes to the classication of mature B- and T-cell lymphomas, including molecular subclassication, will be briey reviewed here and further highlighted in later sections. In the updated WHO classication, there are a number of new designations in the category of diffuse large B-cell lymphoma (DLBCL), with morphologic, molecular, and immunophenotypical subgroups as well as distinct disease entities recognized. DLBCLnot otherwise specied (DLBCL-NOS) comprises all DLBCL cases that do not belong to specic subtypes or disease entities. It includes morphologic (eg, centroblastic and immunoblastic), molecular (ie, germinal center B-cell like [GCB] and activated B-cell like [ABC]), and immunohistochemical (eg, GCB vs non-GCB) subgroupings (Table 18-4). Specic DLBCL disease subtypes include the new designations primary central nervous system (CNS) DLBCL and EBV-positive DLBCL of the elderly, and in addition, there are a number of recognized lymphomas of large B cells (eg, primary mediastinal large B-cell lymphoma [PMBCL], intravascular lymphoma, lymphomatoid granulomatosis) (Table 18-4). Of note, borderline cases are also distinguished, including an overlapping category between DLBCL and Burkitt lymphoma and an overlapping category between DLBCL and classical Hodgkin lymphoma (CHL) (Table 18-4). Few changes have been introduced to the indolent B-cell lymphoma classication. There are a variety of entities that
Table 18-3 Subtypes of Hodgkin lymphoma. Classical Hodgkin lymphoma Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte-depleted Nodular lymphocyte-predominant Hodgkin lymphoma
are considered small B-cell clonal lymphoproliferations but that do not fall into the established categories of small B-cell lymphomas, including splenic B-cell lymphoma/leukemia, unclassiable. In addition, a new category called primary cutaneous follicle center lymphoma has been introduced, where patients typically present with solitary lesions on the head and trunk tumors are composed of neoplastic follicle center cells including centrocytes and a variable number of centroblasts. It should be distinguished from primary cutaneous DLBCL, leg type, which is comprised of a diffuse monotonous pattern of centroblasts or immunoblasts, irrespective of site, and is considered aggressive (Table 18-4). For the peripheral T/NK-cell neoplasms, the previously established categories of predominantly leukemia, predominantly nodal, and predominantly extranodal have been eliminated given that the subdivisions were often overlapping. The classication system has been further rened with a number important modications, including recognition of several new distinct and provisional disease categories (Table 18-4). Anaplastic lymphoma kinase (ALK)positive anaplastic large-cell lymphoma (ALCL) is now recognized as a distinct entity and ALK-negative ALCL is a provisional entity (see section on ALCL). The rare peripheral T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma (SCPTCL), is conned to cases with an - phenotype. Several new primary cutaneous PTCL categories have been created due to differences in clinical behavior, including primary cutaneous - T-cell lymphoma, which also includes the - subtype of SCPTCL due to a similar aggressive course. Of note, one entity has been removed from this section of the WHO classication, blastic NK-cell lymphoma, and is listed in a new category called acute leukemias of ambiguous lineage.
Key points
B and T cells undergo maturation in the bone marrow and thymus, respectively. Both B and T cells rearrange antigen receptor genes and acquire cell surface markers as they differentiate. B cells may undergo neoplastic transformation during immunoglobulin gene rearrangement, class switch, or somatic hypermutation as a result of errant chromosomal translocation and dysregulation of oncogene expression. Specic patterns of surface marker expression and chromosomal translocation characterize many lymphoproliferative diseases. The WHO classication represents an important advance in characterizing clinical and biologic subtypes of hematologic malignancies Excisional biopsy is critical for accurate diagnosis and hematopathology review for lymphoma classication and management.
Overview of lymphocyte development | 515
Table 18-4 World Health Organization classication of B-cell and T-cell neoplasms. B-cell neoplasms T-cell neoplasms Precursor B-cell neoplasms* Precursor T-cell neoplasms* B lymphoblastic leukemia/lymphoma NOS T lymphoblastic leukemia/lymphoma B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities Mature B-cell neoplasms Aggressive lymphomas Diffuse large B-cell lymphoma: variants, subgroups and subtypes/entities Diffuse large B-cell lymphoma, NOS Common morphologic variants: centroblastic, immunoblastic, anaplastic Rare morphologic variants Molecular subgroups: germinal center B-cell like (GCB) and activated B-cell like (ABC) Immunohistochemical subgroups: CD5 DLBCL, GCB, and non-GCB Diffuse large B-cell lymphoma subtypes T-cell/histiocyte-rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV-positive DLBCL of the elderly Other lymphomas of large B cells Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma DLBCL associated with chronic inammation Lymphomatoid granulomatosis ALK-positive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma arising in HHV-8associated multicentric Castleman disease Primary effusion lymphoma Borderline cases B-cell lymphoma, unclassiable, with features intermediate between DLBCL and Burkitt lymphoma B-cell lymphoma, unclassiable, with features intermediate between DLBCL and classical Hodgkin lymphoma Burkitt lymphoma Mantle cell lymphoma Indolent lymphomas Follicular lymphoma Primary cutaneous follicle center lymphoma Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) Nodal marginal zone lymphoma Splenic marginal zone lymphoma Splenic B-cell lymphoma/leukemia, unclassiable Lymphoplasmacytic lymphoma Heavy chain disease Plasma cell neoplasms CLL/SLL B-cell prolymphocytic leukemia Hairy cell leukemia Mature T-cell neoplasms Aggressive lymphomas T-cell prolymphocytic leukemia Aggressive NK-cell leukemia Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, ALK positive Anaplastic large-cell lymphoma, ALK negative Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Adult T-cell leukemia/lymphoma Primary cutaneous - T-cell lymphoma Primary cutaneous CD8 aggressive epidermotropic T-cell lymphoma
Indolent lymphomas T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorders of NK cells Mycosis fungoides Szary syndrome Primary cutaneous CD30 T-cell lymphoproliferative disorder Primary cutaneous CD4 small/medium T-cell lymphoma
*All precursor neoplasms are considered aggressive. Course is usually indolent but in some cases is aggressive. CLL chronic lymphocytic leukemia; CNS central nervous system; DLBCL diffuse large B-cell lymphoma; HHV-8 human herpesvirus 8; NK natural killer; NOS not otherwise specied; SLL small lymphocytic lymphoma.
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Non-Hodgkin lymphomas
The non-Hodgkin lymphomas (NHLs) are a biologically and clinically heterogeneous group of lymphoproliferative diseases that reect the diverse cell types comprising our immune system. These neoplasms are characterized by the clonal expansion of malignant cells of B-cell, T-cell, NK-cell, or, rarely, histiocytic/dendritic-cell origin. The natural history, prognosis, and therapeutic approach for an individual with NHL depend on the specic subtype of lymphoma and the clinical stage; thus, accurate diagnosis and staging are essential to optimal management. Classication The WHO classication of the tumors of hematopoietic and lymphoid tissues, based on the earlier Revised European-American Lymphoma (REAL) classication, represents an important advance in dening hematologic malignancies and was the rst lymphoma classication to integrate morphologic, immunophenotypic, molecular genetic, and clinical features to dene individual entities. The third edition of the WHO classication served to update the REAL and add several new entities, and the recently published fourth edition of the WHO classication has rened the classication further as our understanding of lymphoid neoplasms has expanded over the last decade (Swerdlow et al, 2008). As described above, NHLs are divided into precursor and mature B- or T/NK-cell categories (Table 18-4). Overall, approximately 90% of all NHLs in Western countries are of mature B-cell origin, with DLBCL and follicular lymphoma being the most common subtypes. In children, HL is more predominant, and the aggressive NHLs of lymphoblastic lymphoma, Burkitt lymphoma, and DLBCL are much more commonly encountered than indolent neoplasms. The incidence of NHL is lower among Asian populations, in whom T-cell neoplasms are more frequent. For clinical purposes, the NHLs can be broadly separated into indolent or aggressive categories (Table 18-4). Indolent lymphomas are generally incurable with most standard therapeutic approaches and are typied by a chronic course with repeated relapses and progression with standard therapy. However, some of these patients survive many years with remarkably stable disease even in the absence of specic therapy. Median survival is usually 8 to 10 years but not uncommonly may exceed 15 to 20 years. Most, but not all, aggressive lymphomas are potentially curable with combination chemotherapy. Aggressive subtypes usually have a more acute presentation often with B-symptoms and a more rapid progression than the indolent entities. In the event of failure to achieve complete remission following treatment or with
relapse after an initial therapeutic response, survival is usually measured in months rather than years. Some of these patients, however, are cured by second-line chemotherapy and stem cell transplantation approaches, as described later in this chapter. Epidemiology, pathogenesis, and molecular characterization Data from cancer registries show that the incidence of NHL has been steadily increasing in North America, Europe, and Australia at a rate of approximately 2% to 3% per year for the past 30 years. Over 65,000 new cases of NHL were diagnosed in the United States in 2009, compared with approximately 8000 cases of HL, making NHL the sixth most common cancer in adult men and fth in adult women. The reasons for this increasing incidence are unknown but are the subject of ongoing epidemiologic investigations. Associations have been made with occupational exposure to certain pesticides and herbicides (Table 18-1). Agricultural workers with cutaneous exposure to these agents have an approximately 2- to 6-fold increased incidence of NHL, possibly contributing to the relatively greater frequency of lymphoma in rural versus urban populations. In children, NHL accounts for approximately 8% of all childhood cancers. Immunosuppression associated with human immunodeciency virus (HIV) infection or iatrogenically induced immune suppression in the organ transplantation setting is associated with an increased incidence of aggressive B-cell lymphomas, likely due to dysregulated B-cell proliferation and susceptibility to viruses such as EBV (Table 18-1). In some cases, these neoplasms are polyclonal and may respond to reduced immunosuppression when feasible after transplantation. More subtle, chronic immunoregulatory disorders such as rheumatoid arthritis, Sjgren syndrome, and Hashimoto thyroiditis also carry an increased risk of NHL. In children, the incidence of NHL is increased in several disorders that have in common immunodeciency from primary immune disorders, including ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable or severe combined immunodeciency, and X-linked lymphoproliferative disorder. In general, there is no particular predilection for lymphoma among specic ethnic groups, although NHL is more frequent in Western than in Asian populations. Familial predisposition to NHL is rare; however, kindreds with high frequencies of NHL have been reported. In particular, CLL and Waldenstrm macroglobulinemia are seen more frequently in rst-degree relatives. Infection with the bacterium Helicobacter pylori is strongly associated with gastric MALT lymphoma. Interestingly, patients with MALT limited to the stomach often achieve complete remission following successful therapy to eradicate
Non-Hodgkin lymphomas | 517
H pylori, indicating that the lymphoma remains dependent in part on continued antigenic drive. Recently, associations have been made between orbital infection by Chlamydia psittaci and orbital adnexal MALT lymphoma, infection with Campylobacter jejuni and immunoproliferative small intestinal disease, and Borrelia burgdorferi and cutaneous MALT lymphoma. These intriguing associations need to be rmly established by additional investigation, including assessment of lymphoma regression following eradication of the infectious agent. Certain viral infections have been linked with specic subtypes of NHL. EBV has a clear pathogenic role in endemic as well as some cases of sporadic Burkitt lymphoma and in many cases of HIV-related aggressive B-cell lymphoma. EBV is also strongly associated with extranodal NK/T-cell lymphoma, nasal type most commonly seen in Asia and in Central and South America. It is also detected in 70% to 80% of cases of angioimmunoblastic T-cell lymphoma (AITL); however, its role, if any, in disease pathogenesis is unknown. A new entity in the 2008 WHO classication classies a DLBCL of the elderly that is EBV-associated. Evidence of EBV is also seen at a moderate frequency in HL, particularly the mixed cellularity subtype; however, a direct causal link has not yet been proven. The -herpesvirus HHV-8 (Kaposi sarcomaassociated herpesvirus [KSHV]) was rst described in Kaposi sarcoma but also has been associated with an unusual primary body cavity lymphoma (primary effusion lymphoma) most commonly seen in patients with acquired immunodeciency syndrome (AIDS). HHV-8 has also been described in association with multicentric Castleman disease. The retrovirus human T-cell lymphotropic virus 1 (HTLV-1) is associated with adult T-cell leukemia/lymphoma endemic to Japan, central Africa, and the Caribbean. Chronic hepatitis C virus infection has been linked to the development of lymphoplasmacytic lymphoma. Studies using highly sensitive PCR techniques have reported that approximately 40% of NHL, primarily diffuse large B-cell and follicular histologies, have detectable simian virus 40 (SV40) sequences. SV40 was found to be a contaminant of polio vaccines administered in the late 1950s and early 1960s, and it has been suggested that this exposure may be a contributing factor to the increasing occurrence of NHL. However, these SV40 ndings need to be veried in additional studies before causation is established. Specic chromosomal translocations are strongly associated with individual subtypes of B-cell NHL (Table 18-2). The majority of these arise early in B-cell differentiation during the process of immunoglobulin gene rearrangement, when errant fusion of immunoglobulin promoter and enhancer elements with other genes leads to dysregulated oncogene expression. Careful study of such translocations has provided important insights into pathogenetic mechanisms
in lymphoma. The most frequent of these translocations are (i) t(14;18), with resultant overexpression of the antiapoptotic gene BCL2, which is present in 85% of follicular lymphomas; (ii) t(11;14) with cyclin D1 overexpression, which is present in virtually all MCLs; and (iii) t(8;14), t(2;8), and t(8;22) of Burkitt lymphoma, which fuse an immunoglobulin heavy or light chain gene promoter to the CMYC transcription factor. BCL6, a chromosome 3 transcription factor gene capable of promiscuous rearrangement with multiple translocation partners, is most commonly identied in DLBCL. It has been reported that lymphomas that overexpress BCL6 mRNA or protein, either as a result of chromosomal translocation or another mechanism, may have a better prognosis for survival compared with those that are BCL6 negative. The t(2;5)(p23;q35) fuses the ALK gene with nucleophosmin, the nucleophosmin promoter, and is associated with Ki-1 (CD30)-positive ALCL. Several other translocation partners for ALK also have been described in this disease. This translocation and ALK expression are associated with a more favorable prognosis in ALCL (see also section on peripheral T-cell lymphomas). Gene signatures in lymphoma The diagnostic accuracy of lymphomas is now signicantly improved; however, within any given lymphoma subtype, there is a diverse spectrum of clinical behavior that reects the underlying molecular genetic alterations inherent within tumor cells. For example, even those disease entities dened by specic genetic abnormalities that are important in disease initiation [eg, t(14;18) in follicular lymphoma] have additional aberrant pathways composed of multiple genes that contribute to the malignant phenotype. The recent sequencing of the human genome facilitates more genome-wide approaches using large-scale gene expression analyses that have been applied to simultaneously monitor the expression of thousands of genes from human tumor samples. Such studies have the potential to further rene the classication of heterogeneous disease sets, dene molecular signatures of prognosis, and elucidate novel therapeutic targets. Multiple techniques have been developed to analyze the expression of a large number of genes, but microarrays have emerged as the most commonly used method. Oligonucleotide arrays are commonly used today, and the most widely used is the Affymetrix chip (Affymetrix, Santa Clara, CA), which is composed of 25-mers that overcome the difculty of cross-hybridization by having multiple probes representing each transcript and inclusion of a second oligonucleotide probe that contains a single variant in the center of the probe (Ramaswamy et al, 2002). With the
518 | Lymphomas
availability of the full human genome sequence, currentgeneration chips are representative of all known genes. Furthermore, investigators wishing more customized arrays can have them individually built. There are 2 main approaches to gene expression data analysis: unsupervised and supervised learning. In unsupervised learning, samples are aggregated into groups based on the overall similarity of their gene expression proles without any a priori knowledge of the sample labels, thus facilitating class discovery. In contrast, in supervised learning, tumors are grouped based on known differences, and a model can then be trained to distinguish between 2 classes. Incorporation of both of these techniques and various array platforms described has been instrumental to our current understanding of lymphoid biology. Furthermore, multivariate models can also be used if clinical data are available to correlate specic gene signatures and prognosis. This technology has provided new insights into biologically and clinically relevant subsets of lymphoma, as well as being a tool for gene discovery and identication of novel therapeutic targets. These insights are discussed with the relevant NHL entities later in the chapter. Staging and prognostic factors Staging procedures dene the anatomic extent of the disease and generally include careful physical examination for lymphadenopathy and organomegaly; computed tomography (CT) scans of the neck, chest, abdomen, and pelvis; and bone marrow biopsy. CT or magnetic resonance imaging (MRI) of the brain and evaluation of the cerebrospinal uid are indicated in patients with Burkitt or lymphoblastic lymphomas and should also be considered in patients with aggressive histology lymphoma involving the bone marrow, paraspinal region, sinonasal region, or testis. The Ann Arbor staging system, identifying patients as having stage I (localized) to stage IV (extensive) disease, was originally
devised for use in HL but was later adopted for use in NHL. Patients are further stratied as to the absence (A) or presence (B) of symptoms, namely, fevers, drenching night sweats, or weight loss of 10% or more within 6 months of diagnosis (Table 18-5). Several limitations become apparent when the Ann Arbor classication is applied to NHL. Unlike HL, which has a contiguous pattern of lymphatic involvement, NHLs have a tendency to spread hematogenously and involve noncontiguous lymph node sites. In addition, the Ann Arbor staging system does not reect the unique natural history of specic NHL subtypes or the consequences of lymphomatous involvement of certain extranodal disease sites (eg, sinus, CNS, testicular). In addition, important factors reecting tumor burden (eg, lactate dehydrogenase [LDH], number of nodal or extranodal sites involved, tumor bulk, 2-microglobulin, B-symptoms) and physiologic reserve of the patient (eg, age, performance status) are not included in this conventional staging system. To more fully incorporate additional relevant prognostic features, more broadly relevant models have been developed in the most common NHLs, DLBCL and follicular lymphoma. The most widely used clinical prognostic model to stratify patients with aggressive NHLs is the International Prognostic Index (IPI) (Shipp et al, 1993). Institutions from all over the world provided clinical and laboratory information on patients with aggressive large-cell lymphoma diagnosed by the Working Formulation, Kiel, and Rappaport classications, and thus, immunophenotyping information was not available or incorporated into the model. Based on disease frequency, the most common subtype submitted for the development of the IPI would have been DLBCL. The purpose was to identify pretreatment variables that predict relapse-free and overall survival (OS) with doxorubicincontaining combination chemotherapy. The following 5 risk factors were independently associated with clinical outcome
Stage I II
Denition Involvement of a single lymph node or of a single extranodal organ or site (IE) Involvement of 2 or more lymph node regions on the same side of the diaphragm, or localized involvement of an extranodal site or organ (IIE) and 1 or more lymph node regions on the same side of the diaphragm Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by localized involvement of an extranodal organ or site (IIIE) or spleen (IIIS) or both (IIISE) Diffuse or disseminated involvement of 1 or more distant extranodal organs with or without associated lymph node involvement
Table 18-5 Ann Arbor staging system.*
III
IV
*Fever
38C, night sweats, and/or weight loss 10% of body weight in the 6 months preceding admission are dened as systemic symptoms. The spleen is considered nodal.
Table 18-6 International Prognostic Index (IPI) and age-adjusted index for aggressive lymphoma patients treated with doxorubicin-containing combination chemotherapy.
Risk group All ages* Low (L) Low-intermediate (LI) High-intermediate (HI) High (H) Age-adjusted index (60) Low (L) Low-intermediate (LI) High-intermediate (HI) High (H)
*IPI Age-adjusted
Risk factors (no.) 0, 1 2 3 4, 5 0 1 2 3
Distribution of cases (%) CR rate (%) 5-year OS (%) 35 27 22 16 22 32 32 14 87 67 55 44 92 78 57 46 73 51 43 26 83 69 46 32
risk factors are age 60 years, LDH normal, PS 2, stage III or IV, and 1 extranodal sites. IPI risk factors are age 60, LDH normal, PS 2, and stage III or IV. Shipp MA, Harrington DP, Anderson JR, et al. A predictive model for aggressive non-Hodgkins lymphoma. The International Non-Hodgkins Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994. CR complete remission; LDH lactate dehydrogenase; OS overall survival; PS performance status.
and are often referred to as APLES: (i) age 60; (ii) performance status 2; (iii) elevated serum LDH; (iv) number of extranodal sites of disease 1; and (v) stage III or IV. The IPI score is derived as a simple additive score from 0 to 5 and has been widely adopted to estimate prognosis in patients with NHL (Table 18-6). Four prognostic risk categories were identied that had the following 5-year OS rates: low risk, 0 to 1 factor 73%; low-intermediate risk, 2 factors 51%; high-intermediate risk, 3 factors 43%; and high risk, 4 to 5 factors 26%. Of note, these survival estimates are prior to the use of rituximab. An age-adjusted score has been developed for patients 60 years of age, where stage, performance status, and elevated LDH, but not extranodal disease, correlate with outcome (Table 18-6). It is recognized that these clinical IPI factors likely represent surrogate markers of the underlying biology of the lymphoma. Other serum and tumor markers, plus recent cDNA microarray analyses, hold promise to provide additional insights into pathogenesis and prognosis that in the future may have clinical utility to develop the treatment approach for individual patients. The IPI score is also predictive of survival in indolent lymphomas, namely
Table 18-7 Comparison of the Follicular Lymphoma International Prognostic Index (FLIPI) and the International Prognostic Index (IPI) in follicular lymphoma. Risk model and group FLIPI Low Intermediate High IPI Low Low-intermediate High-intermediate High OS overall survival.
follicular lymphoma, although using the IPI, the majority of these patients fall into the low- or low-intermediaterisk categories (Table 18-7). As such, a new index was developed specically for follicular lymphoma called the Follicular Lymphoma International Prognostic Index (FLIPI) in hopes of better stratifying patients by risk. This index is often remembered by No-LASH. The 5 clinical factors that are the strongest predictors of outcome in multivariate analysis are age 5 nodal sites of disease, elevated LDH, age 60 years, stage III or IV disease, and hemoglobin 10 g/L. Compared with the IPI, the FLIPI provides a better distribution of patients across the risk categories of good risk (0 to 1 factor), intermediate risk (2 factors), or poor risk (3 factors) (Table 18-7). The 5- and 10-year OS rates were 90% and 70%, respectively, for good-risk patients but decreased to 53% and 36%, respectively, for poor-risk patients (Table 18-7). Although the IPI scoring system provides useful prognostic information, there is no denitive evidence that outcome is altered by using intensive regimens in high-risk patients. Numerous studies have been reported, and others are still in progress, assessing the utility of the IPI and risk-adjusted or risk-adapted therapeutic strategies. These include trials
Distribution of cases (%) 36 37 27 49 31 15 5 5-year OS (%) 91 78 53 88 71 57 44 10-year OS (%) 71 51 36 67 50 28 36
No. of factors 01 2 3 01 2 3 45
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Histology Routinely FDG avid DLBCL HL Follicular NHL MCL Variably FDG avid Other aggressive NHLs Other indolent NHLs
*Recommended Recommended
Pretreatment Mid-treatment Response assessment Posttreatment surveillance Yes* Yes* No No No No Clinical trial Clinical trial Clinical trial Clinical trial Clinical trial Clinical trial Yes Yes No No No No No No No No No No
Table 18-8 Recommended timing of PET/CT scans in lymphoma clinical trials.
but not required before treatment. only if ORR/CR is a primary study end point. Recommended only if PET is positive before treatment. CR complete remission; CT computed tomography; DLBCL diffuse large B-cell lymphoma; FDG uorodeoxyglucose; HL Hodgkin lymphoma; MCL mantle cell lymphoma; NHL non-Hodgkin lymphoma; ORR overall response rate; PET positron emission tomography.
of high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) for aggressive lymphoma patients with high IPI scores; however, such strategies are not currently established as standard approaches and remain experimental. The IPI is useful in comparing studies and also in the investigation of new prognostic factors to determine the independent effect on outcome. The use of positron emission tomography (PET) scanning is proving increasingly useful both for staging and assessing response to lymphoma therapy. The International Harmonization Project in lymphoma has recently outlined recommendations on the role of PET scans in staging and response assessment (Juweid et al, 2007). PET scanning in the curative lymphomas, DLBCL and HL, is recommended because it will facilitate assessment of disease extent and also provide a pretreatment comparison for response assessment (Table 18-8). However, given that PET is not widely available, it is not absolutely required. Residual abnormalities on CT scans frequently lead to a partial remission assessment, although it is recognized that many of these patients may in fact be in a complete remission (CR) (PET negative) and that the abnormal tissue visualized may represent brosis rather than residual lymphoma (Cheson et al, 2007). PET scanning in such cases may provide evidence for a functional CR. Several recent reports have suggested that the achievement of early PET negativity, for example, after only 2 to 4 cycles of treatment, may be highly predictive of very low relapse rates in aggressive lymphoma (Spaepen et al, 2002). In one comprehensive analysis where treatment was not modied based on the PET results, the 2-year event-free survival (EFS) rate was 0% to 35% if the mid-treatment PET was positive compared with 72% to 93% if the mid-treatment PET was negative (Kasamon and Wahl, 2008). Overall, relapse or progression occurs in 71% to 100% of patients with a positive mid-treatment PET. However, whether PET scanning can be used to alter therapy is the subject of
ongoing clinical trials, and thus the use of mid-therapy PET scans should be restricted to use in clinical trials. Furthermore, the specicity of a PET scan is not 100% because uptake can occur in the setting of inammation, including granulomatous disease and infection, and a biopsy should be performed in a PET-positive patient in a remission by CT scan if HDT and SCT are under consideration. Patient follow-up Patient surveillance following treatment of lymphoma should address both long-term complications of therapy and disease recurrence. Long-term effects of therapy depend on the type of treatment and whether radiotherapy was also administered. Radiotherapy to the head and neck region leads to decreased salivation with dental caries; thus, close dental follow-up should be performed. Additionally, if the thyroid was included in the radiation eld, a large proportion of patients may eventually become hypothyroid and the thyroid-stimulating hormone level should monitored with each follow-up visit. Women who have had mantle radiation should receive a mammogram 10 years after radiation or at age 40. Long-term survivors are also at risk of second malignancies. Once primary therapy has been completed and remission documented, patients are typically followed every 3 months for the rst 2 years, then every 6 months until 5 years, and then annually thereafter. Most recurrences of aggressive lymphoma occur in the rst 2 years after treatment, although late relapses beyond 5 years do occur in a small minority of patients. Patients with indolent lymphoma have a lifelong risk of relapse and are typically seen every 3 months for the rst 2 years and then every 3 to 6 months indenitely. There is no evidence that routine CT imaging impacts outcome in the surveillance of patients (Weeks et al, 1991), because most relapses are detected by patients or their
physicians based on the development of new symptoms or signs. However, it can be considered in high-risk young patients with curable lymphomas. Currently, there are insufcient data to support the use of routine uorodeoxyglucose PET in the follow-up of patients with lymphoma.
Key points
NHLs are biologically and clinically heterogeneous; accurate diagnosis using the WHO classication is essential to optimal management. The majority of NHLs are of B-cell origin and are broadly categorized as indolent versus aggressive subtypes. The incidence of NHL is increasing 2% to 3% per year in Western countries. Specic chromosomal translocations are associated with specic subtypes of lymphoma and are pathogenetically involved in malignant transformation and progression. The IPI score provides important prognostic information for outcome and survival in both aggressive and indolent lymphomas. The FLIPI has been developed specically for follicular lymphoma.
Indolent B-cell NHL The indolent B-cell lymphomas include the cell types shown in Table 18-4, and the most commonly encountered subtype is follicular lymphoma, which accounts for 20% of all lymphomas. Other subtypes include marginal zone lymphomas, including extranodal marginal zone lymphomas, or what was previously referred to as MALT lymphomas, and lymphoplasmacytic lymphoma. This category also includes CLL/SLL, discussed separately in Chapter 19. Follicular lymphoma Follicular lymphomas are derived from germinal center B cells and are graded based on the number of centroblasts per high-power eld: grade 1 (0-5); grade 2 (6-15); and grade 3 (15). The tumor cells are CD20, CD10, BCL6, BCL2, and CD5. Up to 90% of follicular lymphomas have a t(14;18) with a higher frequency observed in grade 1 or 2 follicular lymphomas. Many clinicians distinguish between follicular grade 1 or 2 and grade 3 and treat the latter with anthracycline-based chemotherapy, but data are discrepant as to whether a clear plateau can be seen in the survival curve. This suggests that cure is possible in patients with grade 3 follicular lymphoma or follicular large-cell lymphoma, the latter term referring to the designation in earlier classications. Furthermore, in the third edition of the WHO classication, grade 3A (centrocytes present) was distinguished from grade 3B (solid sheets of centroblasts), and there may be important clinical and biologic differences within this category.
Abnormalities of 3q27 and/or BCL6 rearrangement are more commonly found in grade 3B cases. Follicular grade 3B may behave more like DLBCL; however, as a result of only relatively recent recognition in the WHO classication, clinical studies of the natural history and outcome differences compared with the other grades of follicular lymphoma are limited. In the updated WHO classication, there are a number of identied variants of follicular lymphoma. Primary intestinal follicular lymphoma, which primarily occurs as localized disease in the small intestine, particularly the duodenum, is one such variant. Other extranodal follicular lymphomas and pediatric follicular lymphoma are also considered variants. Of note, primary cutaneous follicular center lymphoma, a provisional entity in the updated WHO classication, should be distinguished from follicular lymphoma. It is derived from follicle center cells including centrocytes and a variable number of centroblasts and can have a follicular, follicular and diffuse, or diffuse growth pattern. It typically occurs as solitary or localized skin lesions on the scalp, forehead, or trunk, and only 15% present with multifocal lesions. Gene expression proling has been explored in follicular lymphoma to determine whether molecular subgroupings could be identied that have prognostic signicance. In the largest study, whole tumor biopsies of 191 untreated patients with follicular lymphoma were used, and RNA was hybridized to the U133A and U133B microarrays. Using a supervised method to determine signature patterns associated with survival, a molecular signature was constructed that could divide patients into 4 quartiles with widely disparate median survival times (3.9, 10.8, 11.1, and 13.6 years; Dave et al, 2004). Interestingly, the signatures largely consisted of nonmalignant cells from the microenvironment. One signature was termed immune response-1 and was associated with a more favorable prognosis and had high expression of genes expressed in T cells. In contrast, immune response-2 had high expression of genes expressed in monocytes and/or dendritic cells. Whether these signatures can be used to develop new targeted therapies or are still relevant in rituximab-treated patients is unknown.
Management of patients with localized follicular lymphoma
The standard management of stage I and some stage II patients with typically nonbulky, follicular lymphoma consists of radiotherapy alone, using involved-eld or extendedeld irradiation. There are no randomized or comparative studies of these 2 radiotherapy approaches, but there is no clear evidence that OS is improved by more extensive radiation elds. In addition, late-onset radiation-induced second primary cancers remain a concern and are increased in patients with more extensive elds. MacManus and Hoppe
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(1996) found that approximately 40% of limited-stage patients with follicular lymphoma remained disease free at 10 years after radiation treatment; late relapses beyond 10 years were unusual. Other studies also reported a 10-year disease-free survival rate of approximately 40% to 50%, suggesting that cure is possible in a proportion of patients with this approach (Wilder et al, 2001; Campbell et al, 2009). Recent data also support that radiation elds can be reduced without impacting outcome (Campbell et al, 2009). An alternative approach is the use of combined-modality therapy with chemotherapy plus involved-eld radiation (IFRT), although no randomized studies demonstrate that there is an added benet of chemotherapy in early-stage indolent NHL. A recent Stanford report of stage I and II patients with follicular lymphoma who received no initial therapy showed that over half of the 43 patients did not require therapy at a median of 6 or more years of follow-up, emphasizing the indolent course for many patients with this presentation.
signicant comorbid disease. Treatment with palliative intent is indicated for this individual but must take into account his age and generally poor health. It is important that the primary care physician also be involved in the patients care to optimize his cardiac status and discuss the best timing of initiating therapy with his competing comorbidities. An increasing array of therapeutic options are available for advanced-stage follicular lymphoma, ranging from single-agent chemotherapy, which today is uncommonly used, to a variety of combination chemotherapy regimens to newer approaches with monoclonal antibody therapy alone or in combination with cytotoxic drugs. Additional options include HDT with stem cell rescue for selected patients and targeted radioimmunotherapy. This discussion will focus on some of the benets and limitations of traditional versus newer approaches, but the reader should recognize that this is a dynamic and rapidly evolving eld of clinical investigation with considerable promise for favorably altering the natural history of follicular and other indolent lymphomas.
Primary therapy of advanced-stage follicular lymphoma
Clinical case
A 78-year-old man with a history of angina and insulindependent diabetes is referred for evaluation of bilateral cervical adenopathy. He has been more fatigued in recent weeks and has noted several episodes of angina responsive to nitroglycerin. He denies fevers, night sweats, and weight loss. Eastern Cooperative Oncology Group (ECOG) performance status is 2. Examination conrms 2- to 3-cm bilateral cervical adenopathy as well as bilateral axillary and inguinal adenopathy that is causing some mild discomfort. The spleen is palpable 3 cm below the costal margin. Laboratory studies show a normal LDH and normal renal and hepatic function. The hemoglobin is 11.5 g with a normal white blood cell count and platelet count. Excisional biopsy of a cervical node shows replacement by grade 1 follicular lymphoma positive for CD20, CD10, and light chains. Bone marrow biopsy is positive for lymphoma. FLIPI score is 3 (age, stage, and number of nodal sites 4).
Patients with indolent lymphoma are generally of older age and usually present with advanced-stage disease that is very responsive to chemotherapy but not curable with standard therapeutic approaches. In the few randomized controlled studies that are available, it has not been shown that early treatment of asymptomatic advanced-stage patients improves survival, so a common approach in such patients who also have nonthreatening, typically nonbulky disease is watchful waiting and treatment when symptoms or disease progression become apparent. However, it is important that patients be evaluated at regular intervals and are educated as to the signs and symptoms of progressive disease. The patient presented in the clinical case has symptomatic stage IV follicular lymphoma with fatigue, anemia, high-risk FLIPI score, and
The majority of patients enrolled into clinical trials for indolent lymphomas have follicular lymphoma. There are no randomized clinical trials specically in the more uncommon indolent lymphomas, and results are often extrapolated to these other groups. For the purposes of this review, the data will focus on follicular lymphoma, but the principles and therapy approaches can be applied, for the most part, to the other subtypes. The median survival for patients with follicular lymphoma is approximately 9 years; however, this number can vary depending on the FLIPI score. As described, prior studies have found no clear survival benet to initiating chemotherapy in asymptomatic patients with nonthreatening disease; thus, the watch-and-wait approach is still an appropriate approach to these patients (Ardeshna et al, 2003). When patients require systemic therapy, there are a number of existing options. The standard rst-line therapy for advanced-stage indolent lymphoma is alkylator-based chemotherapy. Single-agent therapy with oral chlorambucil or cyclophosphamide delivered in varying schedules, with or without prednisone, will palliate symptoms in most patients, although few achieve CR. Such regimens are useful for elderly patients and those with signicant comorbidities, as in the earlier clinical case. Thus, oral chlorambucil or cyclophosphamide would be a reasonable approach for the patient in the clinical case; prednisone should be withheld in view of his diabetes unless close monitoring is assured. Combination chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); udarabine in combination with cyclophosphamide or cyclophosphamide
Table 18-9 Chemotherapy combinations used in the treatment of non-Hodgkin lymphomas in the primary and relapsed setting. Newly diagnosed patients CVP Cyclophosphamide Vincristine Prednisone CHOP Cyclophosphamide Doxorubicin Vincristine Prednisone R-CHOP CHOP rituximab Relapsed and refractory patients ICE Ifosfamide Carboplatin Etoposide DHAP Dexamethasone High-dose cytarabine Cisplatin GDP Dexamethasone Gemcitabine Cisplatin ESHAP Etoposide Methylprednisolone High-dose cytarabine Cisplatin
MACOP-B Methotrexate/leucovorin Doxorubicin Cyclophosphamide Vincristine Prednisone Bleomycin M-BACOD Methotrexate/leucovorin Bleomycin Doxorubicin Cyclophosphamide Vincristine Dexamethasone ProMACE-CytaBOM Prednisone Doxorubicin Cyclophosphamide Etoposide Cytarabine Vincristine Prednisone Bleomycin
EPOCH Etoposide Vincristine Doxorubicin Cyclophosphamide Prednisone
and mitoxantrone (FC or FCM) (Table 18-9); and numerous other regimens have been shown to increase response rates compared with single agents but have not been established in randomized controlled trials to improve OS. These combination chemotherapy approaches are often used in younger patients in whom the goal is to achieve a more durable remission. They are also useful in the setting of bulky, rapidly progressing, or highly symptomatic disease where a quick response is desirable. Local radiation therapy can be useful for control of locally bulky or obstructing disease that fails to respond adequately to chemotherapy. Furthermore, there are no published randomized controlled trials demonstrating an OS benet of one combination over another in
the primary therapy of follicular lymphoma; thus, practices vary around the world. Rituximab, an anti-CD20 chimeric monoclonal antibody, is a targeted monoclonal antibody that has improved outcomes in virtually all B-cell lymphomas, both indolent and aggressive subtypes. Targeted monoclonal antibodies have several mechanisms of activity, including activation of complement and antibody-dependent cellular cytotoxicity and induction of apoptosis. Rituximab was initially approved in relapsed follicular lymphoma based on an overall response rate (ORR) of approximately 60% with a median response duration of approximately 1 year (McLaughlin et al, 1998). Rituximabs nonoverlapping toxicities, differing mechanisms of action, and in vitro synergy with chemotherapy have led to numerous trials evaluating chemotherapy/rituximab combinations. Virtually all of the randomized trials have demonstrated improved responses for concurrent rituximab/ chemotherapy combinations compared with chemotherapy alone or sequential chemotherapy and rituximab. One of the rst published studies evaluating a rituximab/ chemotherapy combination in advanced-stage follicular lymphoma compared CVP to rituximab plus CVP (R-CVP) for a total of 8 cycles and showed that all end points including ORR, time to treatment failure, and progression-free survival (PFS) were improved in the R-CVP arm (Marcus et al, 2005). Longer follow-up conrmed an improvement in 4-year OS in the R-CVP arm (83% vs 77%, P .029; Marcus et al, 2008). The ECOG evaluated the benet of maintenance rituximab in advanced-stage indolent lymphomas, the majority of which were follicular lymphomas. All patients received induction therapy with CVP followed by randomization for patients achieving a CR or partial remission (PR) to scheduled rituximab retreatment 4 times weekly every 6 months for 2 years versus observation (Hochster et al, 2009). A signicant benet was identied in the maintenance rituximab arm with regard to PFS (3-year PFS, 68% maintenance rituximab vs 33% observation; P 4.4 1010) and OS (3-year OS, 92% maintenance rituximab vs 86% observation; one-sided P .05). Similar results have been seen comparing CHOP with rituximab plus CHOP (R-CHOP) (Hiddemann et al, 2005) and rituximab plus mitoxantrone, chlorambucil, and prednisolone with mitoxantrone, chlorambucil, and prednisolone (Herold et al, 2007). Thus, in symptomatic and t patients, rituximab combinations have become routine in the primary treatment of indolent lymphomas. A study by the Southwest Oncology Group (SWOG) evaluating the impact of rituximab on the natural history of advanced-stage follicular lymphoma showed an improvement in survival in more recent studies incorporating rituximab or radioimmunotherapy compared with chemotherapy alone as rst-line therapy (Fisher et al, 2005). This observational analysis suggests that rituximab is prolonging survival
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and changing the natural history of follicular lymphoma; however, it is unknown whether earlier treatment in lower risk, asymptomatic patients will impact outcome. This question is currently the subject of clinical trials. First-line therapy with rituximab alone and the use of rituximab as maintenance therapy are also being investigated. Two phase II studies of rituximab as rst-line therapy, one by Hainsworth et al (2002) incorporating maintenance rituximab therapy every 6 months for 2 years and another by Ghielmini et al (2004, 2009) using an abbreviated maintenance regimen, have shown high response rates and delayed disease progression. In the latter trial, patients who were either treatment naive or relapsed received 1 dose every week for 4 weeks of rituximab; those demonstrating at least stable disease were randomized to either 4 additional doses of rituximab given at 2-month intervals or no further treatment. The results were recently updated with a median follow-up time of 8.9 years, and the EFS in the consolidation arm was 26% at 5 years compared with 10% in the observation arm (Hainsworth et al, 2002; Ghielmini et al, 2000, 2009). Radioimmunotherapy has recently been evaluated in the primary therapy setting of follicular lymphoma in the FirstLine Indolent Trial (FIT), and the rst report was presented at the American Society of Hematology (ASH) 2008 meeting. Patients could receive any alkylator-based induction chemotherapy, and patients who had achieved a response were randomized to observation versus treatment with yttrium-90 (90Y)-ibritumomab tiuxetan (Zevalin) which is targeted against CD20 (Morschhauser et al, 2008). The rst analysis demonstrated an improvement in PFS in the treatment arm. However, few patients were treated with rituximab, and with the established benet of rituximab in this setting, it is unknown whether additional radioimmunotherapy will improve outcome in patients who have received rituximab with their upfront therapy.
Therapy for relapsed and refractory follicular lymphoma
Multiple options exist for the treatment of patients who have failed rst-line therapy, and the decision of what chemotherapy to use depends on a number of factors including the duration of prior response, patient age, and comorbid illnesses. If a durable remission was achieved with alkylator therapy (2 years), it may be used again. Of note, if CHOP was used as rst-line therapy, a ceiling dose for the anthracyclines may have been reached. For shorter remission durations, udarabine can be used. However, it must be used with caution in heavily pretreated or elderly patients due to immunosuppression. Patients are at increased risk of Pneumocystis carinii and reactivation of herpes zoster. Prophylaxis with trimethoprim/sulfamethoxazole and acyclovir should
be considered. Furthermore, if ASCT is considered as a future treatment option, the number of cycles with udarabine should be minimized to avoid stem cell toxicity. Rituximab combinations have also been tested in the relapsed setting, although the current published data only include patients who did not receive rituximab with initial study. A recent study enrolling patients with relapsed follicular lymphoma compared CHOP with R-CHOP, with a second randomization to maintenance rituximab (375 mg/ m2 every 3 months for 8 doses) versus no therapy in patients achieving a response (van Oers et al, 2006). Similar to studies in the primary setting, R-CHOP was superior to CHOP with regard to PFS and OS. Furthermore, patients who received maintenance rituximab, regardless of whether rituximab was received with CHOP therapy, had an improvement in PFS (median, 51.5 months vs 14.9 months; P .001) and OS. This study has established the benet of rituximab maintenance in the relapsed setting. The Primary Rituximab and Maintenance (PRIMA) study is currently evaluating whether the benet of maintenance rituximab can be extrapolated to the primary therapy setting. Radioimmunotherapy targeted to CD20 is also a viable option for patients with indolent B-cell NHL if the bone marrow is minimally involved and disease is not bulky. The 2 approved radioimmunotherapy treatments for relapsed follicular lymphomas are both murine monoclonal antibodies incorporating either radioimmunotherapy with iodine-131 (131I) (tositumomab) or 90Y (ibritumomab tiuxetan). These agents are the most active single agents in the relapsed disease setting, although their use is limited to patients with adequate leukocyte and platelet counts and 25% marrow involvement by lymphoma. Response duration is, on average, 11 to 15 months, and radioimmunotherapy can also be effective in transformed lymphoma. Single-agent rituximab can also be used in relapsed lymphoma, although now that most patients have received it with their primary therapy and maybe on maintenance, few receive for relapsed lymphoma today. The exception is an elderly patient who has failed an alkylator-based regimen. In this situation, it remains a viable treatment option, given its virtual lack of myelosuppression and relatively low adverse effect prole compared with standard second- and third-line chemotherapy regimens. Single-agent rituximab remains an important treatment option for select patients with relapsed indolent NHL. Bendamustine has recently emerged as a highly active agent in indolent lymphomas. It is described as a bifunctional agent that is an alkylator with purine analog characteristics. The mechanism of action of the alkylator component is through activation of a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. It is now approved in the United States for use in patients with
rituximab-refractory indolent B-cell lymphomas and CLL. A 77% ORR was seen in heavily pretreated patients with a response duration of 6 months. Similar results were seen in a pivotal trial of 100 patients. A phase III trial comparing bendamustine plus rituximab to R-CHOP as rst-line treatment of patients with follicular lymphoma, other indolent lymphoma, and MCL was presented at the ASH meeting in 2007, and the second interim analysis was reported last year. With a median follow-up time of 28 months, there was no difference in response rate or EFS, and the toxicity prole favored the bendamustine plus rituximab regimen.
High-dose chemotherapy and ASCT
The use of high-dose chemotherapy with autologous bone marrow or peripheral blood stem cell rescue is being investigated as a therapeutic option in the treatment of indolent lymphomas, especially for higher risk disease in rst or second relapse. van Besien et al (2003) reviewed 904 patients in the International Bone Marrow Transplant Registry who underwent autologous or allogeneic transplantation for follicular lymphoma. Durable remissions could be induced with either technique. Allogeneic transplantation remains the only known curative option; however, a lower 5-year recurrence rate with allogeneic transplantations is offset by a higher treatment-related mortality compared with autologous transplantation, leading to similar 5-year survival rates of 51% to 62%. There is a suggestion of benet for purged versus unpurged autologous transplantations. The randomized CUP (chemotherapy, unpurged high dose therapy [U] or purged high dose therapy [P]) study, in which patients received an ASCT following remission with CHOP-type chemotherapy, suggested an improvement in PFS (P .0037) but not OS (comparing chemotherapy alone with unpurged ASCT and purged ASCT) for ASCT (Schouten et al, 2003). However, these studies were performed prior to the use of rituximab. Further studies, including on the use of monoclonal antibody therapy as an in vivo purge or for consolidation treatment, and improvement in patient stratication are needed to establish the role of these aggressive therapeutic approaches in indolent NHL.
Tumor vaccine approaches
As described earlier, each B cell expresses a unique immunoglobulin molecule, and the variable region contains a unique recombination gene sequence referred to as an idiotype (Id). B-cell lymphomas represent clonal proliferation of lymphocytes, and thus, the immunoglobulin they express is unique for each patient. This observation led to studies exploring active immunization of patients against their own tumor idiotype. In early studies, the tumor-specic idiotype
was isolated from the B-cell lymphoma and fused to a myeloma cell line, resulting in hybrid cells that secreted the tumor-derived immunoglobulins that were then puried to generate a vaccine. Recombinant DNA technology has more recently been used to clone the immunoglobulin variable region from the tumor, which can then be transfected to produce large amounts of idiotype protein in a more efcient and timely manner than the hybridoma methodology. Immune adjuvants such as granulocyte-macrophage colony-stimulating factor (GM-CSF) are given to enhance the immune response. Early testing of this approach in follicular lymphoma suggested that the development of an anti-idiotype response correlated with outcome (freedom from progression, 7.9 years in responders vs 1.3 years in nonresponders; Kwak et al, 1992). Encouraging results from this and other studies led to the development of 3 randomized controlled studies to determine the efcacy of idiotype vaccination (Biovest, Genitope, Favrille; Houot and Levy, 2009). These trials have been reported in abstracts, but the full publications are not yet available. In 2 of the trials (Genitope and Biovest), vaccination occurred following alkylator-type chemotherapy and at least a PR was necessary to proceed to randomization to either vaccine or placebo. These trials initially did not include the addition of rituximab; however, as data emerged regarding the efcacy of rituximab with combination chemotherapy, the Biovest trial was amended in July 2006 to include R-CHOP as an alternative to the cisplatin, doxorubicin, cyclophosphamide, and etoposide chemotherapy. In the third trial (Favrille), patients were rst treated with rituximab, and if stable disease or better was achieved, they proceeded to the vaccine portion. Of note, rituximab has been shown to delay humoral responses, and thus in the latter trial, the vaccine was continued until disease progression. Unfortunately, the results have been somewhat mixed. The Genitope trial failed to meet its primary end point with no difference in PFS between the vaccine arm (idiotypekeyhole limpet hemocyanin plus GM-GSF) and the control arm (KLM [keyhole limpet hemocyanin] plus GM-CSF). However, in subgroup analysis, superior PFS was observed in patients who did mount an immune response, consistent with prior observations (Levy et al, 2008). The Favrille trial was reported at the ASH 2008 meeting and no improvement in time to progression was observed in the vaccine arm (Freedman et al, 2008). In contrast, the Biovest trial was stopped early due to an apparent benet observed in disease-free survival in patients who received the idiotype vaccination and who had achieved a CR (33.8 months vs 21.2 months; P .047). The details of this study are also not yet available for review. Thus, the role of vaccination remains unclear, particularly now that rituximab is routinely incorporated into primary therapy regimens.
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The array of therapeutic options in follicular and indolent lymphomas is thus increasingly complex and ranges from watchful waiting to aggressive chemotherapy/immunotherapy or stem cell transplantation. The management of individual patients therefore requires a thorough understanding of the natural history of these diseases, an assessment of potential risk and benet for a particular therapy, the pathologic subtype of lymphoma, and the clinical features of disease (eg, stage, bulk) and comorbid disease. It is important that the therapeutic goals and treatment algorithm be thoroughly considered and discussed with the patient at diagnosis so that the sequencing of treatment options can be logically applied. Marginal zone lymphomas The WHO classication separates the marginal zone B-cell lymphomas (MZL) into extranodal MZL of MALT, nodal MZL, and splenic MZL. The morphology of these disorders is characterized by an inltrate of centrocyte-like small cleaved cells, monocytoid B cells, or small lymphocytes and may exhibit an expanded marginal zone surrounding lymphoid follicles. The immunophenotype is characterized by expression of CD20 but lack of CD5 or CD10 expression (Table 18-2); this marker prole is useful in distinguishing MZL from SLL, MCL, and follicular lymphoma. MALT lymphomas MALT lymphomas constitute 50% to 70% of all MZLs. They occur in mucosal sites, predominantly gastric or intestinal, and some nonmucosal extranodal sites, including the lung, salivary gland, periorbital or soft tissue, skin, and thyroid. Often these sites are affected by chronic infection or inammation, such as Sjgren syndrome involving the parotid gland or Hashimoto thyroiditis. The typical presentation of MALT lymphoma is an isolated mass in any of these extranodal sites or an ulcerative lesion in the stomach. Clinically, they behave as indolent disorders. At a molecular level, MALT lymphomas are characterized by the t(11;18)(q21;q21) translocation in approximately 40% of cases and, less commonly, the t(1;14)(p22;q32) translocation. Interestingly, these distinct translocations appear to mimic one another in activating the nuclear factor (NF)-B pathway, potentially leading to antigen-independent growth and clonal progression. Trisomy 3 and 3q27 amplication have also been reported as frequent anomalies. The stomach is the most common site of MALT lymphoma. The majority of cases of gastric MALT lymphoma are associated with H pylori infection. Gastric MALT lymphoma is thought to arise as a result of chronic stimulation of the B and T cells in the stomach by H pylori. These
T lymphocytes release cytokines that stimulate the B cells in the marginal zone of the acquired lymphoid follicles, which eventually leads to the emergence of a clonal B-cell neoplasm that, at least in its early stages, is antigen driven by H pylori. Most commonly, these tumors present with a gastric ulcer and occasionally with a gastric mass. At clinical presentation, they are usually conned to the stomach but may involve draining lymph nodes. A remarkable observation has been that up to 70% of gastric MALT lymphomas regress and are cured following effective antibiotic therapy to eradicate H pylori, with a 5- and 10-year OS of approximately 90% and 80%, respectively (Stathis et al, 2009). The most widely used antibiotic regimen is a combination of amoxicillin, omeprazole, and clarithromycin. Metronidazole is an effective alternative antibiotic in patients with a penicillin allergy. Responses can be slow, taking up to 6 months to 1 year. Repeat assessment of H pylori either by histologic examination or a urea breath test is necessary to ensure that the bacteria have been eradicated. Patients failing to remit may have previously unrecognized large-cell transformation or may carry the t(11;18) translocation, which has been associated with resistance to eradication with H pylori therapy. These tumors are usually antigen independent and thus fail to respond to H pylori eradication. In patients who do not respond to antibiotics, IFRT has been highly effective in localized MALT lymphomas with disease-free survival or PFS rates of 80% at 5 and 10 years (Tomita et al, 2009; Tsai et al, 2007). Similar regimens as those used in follicular lymphoma, including rituximab-based combinations, can be used in patients with advanced-stage disease. Nongastric MALT lymphomas usually have an indolent course, including most of the 20% to 25% of patients who present with stage IV disease. Treatment approaches depend on both stage and site of primary involvement and may include surgery, radiation therapy, or chemotherapy. Patients with resected stage IE lesions, as in the lung, may be followed expectantly without systemic or other therapy until evidence of progression. Other localized MALT lymphomas are often treated with radiotherapy with excellent results (Isobe et al, 2007). Nodal MZL Nodal MZL, previously known as monocytoid B-cell lymphoma, also arises from marginal zone B cells. Whenever nodal MZL is diagnosed, a careful history and physical examination should be pursued for a possible coexisting extranodal MALT lymphoma component, which may be identied in up to one third of cases. It more commonly presents with advanced stage than MALT-type MZL, with peripheral and intra-abdominal lymphadenopathy and bone marrow involvement present in 28% to 45% of cases (Arcaini et al, 2009). Evaluation should include endoscopy or other procedures as
clinically indicated. The t(11;18) and t(1;14) karyotypic changes identied in MALT are absent in nodal MZL, and no specic or recurring karyotypic anomaly has been described. IgM monoclonal gammopathy can occur in approximately 10% of cases. HCV infection is reported in up to 25% of patients. Across reported series, the 5-year OS is 60% to 70%; however, the EFS is only 30%, which likely reects more commonly encountered advanced-stage disease. In the recent updated WHO classication, a new category was introducedpediatric nodal MZL, which has distinctive clinical and morphologic characteristics. There is a male predominance (20:1), and patients usually present with localized asymptomatic adenopathy in the head and neck region. Morphologically, the inltrate is similar to that seen in adults, except that progressively transformed germinal centers are often seen. Splenic MZL Splenic MZLs are rare and occur in older individuals approximately 70 years of age. Patients present with splenomegaly in the absence of peripheral node involvement. Splenic MZL may have associated mesenteric or hepatic involvement, and the bone marrow and blood are typically involved. Some cases have been associated with hepatitis C infection, and responses have been reported with clearance of the virus with pegylated interferon and ribavirin (Hermine et al, 2002); similar results have been seen in other indolent B-cell lymphomas with associated HCV infection (Vallisa et al, 2005). Diagnosis is usually based on spleen histology following splenectomy, bone marrow involvement, or the presence of circulating villous lymphocytes. The disease is very indolent, with median survival times exceeding 10 years. Splenectomy is considered the optimal rst-line therapy in symptomatic patients or in the case of cytopenias not felt to be related to bone marrow inltration. Lymphoplasmacytic lymphoma and Waldenstrm macroglobulinemia Lymphoplasmacytic lymphoma (LPL) is dened in the WHO classication as an indolent neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells. The lymphoma cells may express B-cell markers CD19 and CD20 and are CD5 and CD10 negative, much like the MZLs (Table 18-2). They may also express CD25 and CD38, but it is not a consistent nding. Waldenstrm macroglobulinemia (WM) is found in a signicant subset of patients with lymphoplasmacytic lymphoma and is dened as lymphoplasmacytic lymphoma with bone marrow involvement and an IgM monoclonal gammopathy. The disease affects predominantly older patients; however, a familial predisposition can occur
in up to 20% of patients who present at a younger age. Symptoms may be due to tumor inltration (marrow, spleen, liver, and lymph nodes), circulating IgM macroglobulin (hyperviscosity, cryoglobulinemia, or cold agglutinin hemolytic anemia), and tissue deposition of IgM or other proteins (neuropathy, glomerular disease, and/or amyloid) can occur. Coagulopathies result from IgM binding to clotting factors, platelets, and brin. When serum viscosity is signicantly elevated due to the IgM paraprotein, patients may experience visual disturbances, headaches, dizziness, decreased level of consciousness, cardiopulmonary symptoms, or a bleeding diathesis, which constitute the hyperviscosity syndrome. Symptomatic patients with hyperviscosity should be treated promptly with plasmapheresis to lower the circulating monoclonal protein, followed by prompt institution of chemotherapy to control the malignant proliferation and further paraprotein production. The treatment approach to lymphoplasmacytic lymphoma is more like that of indolent lymphoma or CLL than for a plasma cell dyscrasia. Patients without symptoms are best managed by close monitoring without treatment. Prognostic factors at the time of initial treatment associated with decreased survival include age 65 and anemia. The use of these 2 factors can identify those patients at high (2 factors), intermediate (1 factor), and low risk (0 factors). The median survival times in a study of 122 patients for the high-, intermediate-, and low-risk groups were 46, 107, and 172 months, respectively. Recently, treatment guidelines have been put forth from the International Workshop on Waldenstrm macroglobulinemia (Dimopoulos et al, 2009). Given disease rarity, there are no randomized controlled studies to support one rstline regimen over another. Either alkylator-based chemotherapy or nucleoside analogs represent reasonable rst-line options. Vincristine is often omitted due to underlying neuropathy. Response rates of 75% have been observed using the nucleoside analogs udarabine and cladribine in newly diagnosed patients compared with approximately 50% using alkylator-based regimens; however, these regimens have not been compared with alkylators in a randomized clinical trial. Several studies have demonstrated that the anti-CD20 monoclonal antibody rituximab has signicant activity both as initial therapy and in relapsed patients. Rituximab has been combined with other agents including cyclophosphamide and dexamethasone (ORR, 83%), CHOP (PR, 91%), and udarabine/cyclophosphamide (PR, 79% in primarily relapsed disease). Abrupt increases in IgM can occur following rituximab therapy, particularly if the pretreatment IgM level is 5000 mg/dL with worsening symptoms of hyperviscosity (Treon et al, 2004). Recent reports suggest that there may be an increased incidence of transformation and development of myelodysplastic syndrome (MDS)/acute myeloid
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leukemia (AML) in WM patients treated with nucleoside containing therapy (Treon et al, 2009). More recently, thalidomide and lenalidomide have been tested in WM and are highly active agents. The proteasome inhibitor bortezomib is also active in WM with an ORR of 78% to 85%; however, peripheral neuropathy can be problematic. The combination of bortezomib, dexamethasone, and rituximab was evaluated in untreated patients with WM with an ORR of 96%. Autologous or allogeneic transplantation are considered in patients with aggressive high-risk disease. Hairy cell leukemia The typical presentation of hairy cell leukemia is that of a middle-aged man (median age, 50-55 years) with pancytopenia, splenomegaly, cytopenic complications (eg, infections, bleeding), and an inaspirable bone marrow (dry tap). The male-to-female ratio is 3:1 to 5:1. Hairy cell leukemia may be misdiagnosed as myelobrosis, aplastic anemia, or MDS. Hairy cell leukemia is rare, and making the proper diagnosis is crucial because of its generally favorable prognosis, with a 10-year OS exceeding 90%, and the excellent treatment responses to nucleoside analogs. Long-term survivors have been reported to have an increased risk of second cancers, with a cumulative incidence of 30% by 25 years after the diagnosis. The disease is diagnosed by its typical peripheral blood morphology with cytoplasmic hairy projections on the cell surface, a positive tartrate-resistant acid phosphatase stain, and an immunophenotype positive for surface immunoglobulin, CD19, CD20, CD22, CD11c, CD25, and CD103 (Table 18-2). Marrow biopsy demonstrates a mononuclear cell inltrate with a fried egg appearance of a halo around the nuclei and increased reticulin and collagen brosis. Hairy cell leukemia has a unique sensitivity to purine analogs. The nucleoside analogs cladribine or pentostatin are the treatments of choice in hairy cell leukemia in view of the high response rates and durable remissions achieved. Cladribine may be superior because of the short duration of therapy required (the majority of patients remit after a single course of cladribine) and a more favorable toxicity prole. In one large series of 233 patients with long-term follow-up, the response rate with either of these agents was 80%, and median recurrence-free survival was 16 years (Else et al, 2009). Hairy cell leukemia has high-density CD20 expression and thus has been responsive to anti-CD20 monoclonal antibody therapy with rituximab. Rituximab has been used as a single agent in relapsed patients with an ORR of 80% and has also been explored in combination with purine analogs. Splenectomy and interferon alfa were the treatments of choice in years past but have been largely supplanted by these newer approaches.
Transformation to aggressive lymphoma in indolent lymphomas Transformation is the development of aggressive NHL in patients with underlying indolent lymphomas. It most commonly occurs in follicular lymphoma but can occur in any of the indolent lymphomas. The British Columbia Cancer Agency recently reported on the incidence and outcome of 600 patients with follicular lymphoma who subsequently developed transformed lymphoma (Al-Tourah et al, 2008). Diagnoses were either made clinically (sudden increase in LDH 2 the upper limit of normal, discordant nodal growth, or unusual extranodal sites of involvement) (37%) or pathologically (63%). In this series, the annual risk of transformation was 3% per year, with a 10- and 15-year risk of 30% and 45%, respectively. Overall, the median posttransformation survival time was 1.7 years, with superior outcomes observed in limitedstage patients. Similar results were observed in a series from St. Bartholomews, where histologic transformation was observed in 28% of patients with follicular lymphoma by 10 years (Montoto et al, 2007).
Key points
Advanced stage indolent NHL is treatable but not curable with standard chemotherapy. Follicular NHL is the most common indolent NHL. IFRT for stage I and II indolent lymphoma will lead to long-term remission and potentially cure in a subset of patients. Patients with asymptomatic, advanced-stage indolent NHL may be followed without specic therapy to assess the pace of disease; a variety of chemotherapeutic and targeted monoclonal antibody therapies may be used for symptomatic or progressive disease. Newer approaches, including monoclonal antibody plus cytotoxic chemotherapy combinations and stem cell transplantation, hold promise for improved survival in selected patients.
Aggressive B-cell lymphomas The most prevalent of the aggressive lymphomas is DLBCL. Other histologies in this category include MCL, Burkitt lymphoma, lymphoblastic lymphoma, and most of the T- and NK-cell lymphomas (Table 18-4). These neoplasms are characterized by a more acute presentation and, although often curable (except for MCL), are associated with relatively short survival in the absence of therapy-induced remission. This chapter focuses on the mature B- and T/NK-cell neoplasms. For further discussion on B- and T-cell lymphoblastic lymphoma, please see Chapter 17.
Diffuse large B-cell lymphoma DLBCL is composed of large B cells with a diffuse growth pattern. There are number of subtypes that fall under the
Clinical case
A 68-year-old woman is diagnosed with stage IIIA DLBCL, with the largest nodal mass measuring 4 cm in the left internal iliac chain. There is no splenomegaly by examination or CT scan, and bone marrow biopsy is negative. Laboratory studies show a normal complete blood cell count and chemistries except for an LDH elevated 1.5 normal. Her ECOG performance status is 1. Immunophenotypic stains of the lymphoma cells reveal them to express CD19, CD20, light chains, and BCL2 but to be negative for CD10 and BCL6 expression.
survival versus the non-GCB types, and this information may prove useful in developing risk-adapted treatment strategies. The prognostic value of the subtype appears independent of but complementary to the IPI score (see below). However, this molecular technique is currently impractical and not yet widely available for routine clinical use. Hans et al (2004) have recently reported the ability to distinguish GCB versus non-GCB using a small set of immunophenotypic markers: CD10, BCL6, and IRF4/MUM1. Using the cDNA microarray as the gold standard, the sensitivity of the tissue microarray was 71% for the GCB group and 88% for the non-GCB group. However, the results have been inconsistent as to whether this immunophenotypic distinction can be applied to rituximab-treated patients. Currently, cellof-origin information, whether by molecular proling or immunohistochemistry, is not used to direct treatment decisions outside of clinical trials.
Treatment of advanced-stage DLBCL
category of DLBCL but have distinct features that distinguish them as a separate disease category. The new WHO classication recognizes several disease categories of DLBCL including molecular subtypes (GBC and ABC; see later sections), distinct subtypes including T-cellrich B-cell lymphoma or primary CNS lymphoma, and disease entities including PMBCL. Other than primary CNS lymphoma, treatment approaches are similar for the DLBCL subtypes. DLBCL constitutes 25% to 30% of all NHLs and can present with nodal or extranodal disease. Bone marrow involvement occurs in approximately 11% to 27% of cases, but a proportion of these cases are discordant with the presence of a low-grade B-cell lymphoma in the bone marrow. In addition to the B-cell markers CD20 and CD19, the neoplastic cells may also express CD10 (30%-60%), BCL6 (60%-90%), and IRF4/MUM1 (35%-65%). Rare cases may express CD5 (10%) and must be distinguished from the blastoid variant of MCL, which is cyclin D1 positive. Subsets of DLBCL with markedly differing biology and prognoses have been identied using microarray technology, which is capable of analyzing genome-wide expression of thousands of genes. These analyses have identied 2 molecularly distinct subtypes of DLBCL that are recognized as molecular subtypes of DLBCL-NOS: GCB, which has a gene expression prole similar to germinal center B cells; and ABC, which has a prole similar to activated peripheral B cells. Initially a type 3 subtype was identied in an expanded series; however, now it is not felt to represent a distinct subgroup but includes cases that cannot be classied into the GCB and ABC subtypes (Rosenwald et al, 2002). Recurrent chromosomal aberrations have been found to be associated with these subtypes. Gains of 3p, 18q21-22, and losses of 6q21-22 are seen in the ABC subtype, and gains in 12q12 are observed frequently in the GCB subtype. The latter also can also be found to be associated with t(14;18). Importantly, the GCB subtype has an improved
The backbone of treatment of all subtypes of DLBCL is anthracycline-based treatment with CHOP chemotherapy. With this approach, approximately 40% of patients are cured. Dose-intensive second- and third-generation regimens were explored in the 1990s, and although more complex regimens (eg, low-dose methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone [m-BACOD]; prednisone, doxorubicin, cyclophosphamide, and etoposide, followed by cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue [ProMACE-CytaBOM]; and methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) showed promise for improved CR rates and survival in phase II studies, a large cooperative group study revealed that CHOP therapy was equivalent but less toxic than the other regimens, and thus, it remains the standard of care (Fisher et al, 1993). Furthermore, no higher risk subset of patients could be identied who beneted from a regimen other than CHOP. Consequently, the use of these earlier regimens has been largely abandoned, and 6 to 8 cycles of CHOP has become generally accepted as standard therapy. Rituximab has several mechanisms of action, including the ability to sensitize otherwise resistant lymphoma cells to chemotherapy agents in vitro, perhaps in part via downregulation of the Bcl-2 protein. In 2002, Coifer et al (2002) from the GELA group presented preliminary results at the ASH annual meeting plenary session of a phase III clinical trial in which 399 patients 60 to 80 years of age with previously untreated advanced-stage CD20 DLBCL were randomized to receive 8 cycles of standard CHOP chemotherapy or R-CHOP given on day 1 of each 3-week cycle. An improvement
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in all end points including CR rate, EFS, and OS favoring R-CHOP over CHOP was demonstrated. With longer follow-up, the results held, and R-CHOP quickly became the standard of care for advanced-stage DLBCL around the world (Coifer et al, 2002). In a follow-up analysis of outcome based on Bcl-2 protein expression, the benet of R-CHOP appeared largely restricted to the Bcl-2positive subset. A similar study carried out by the US ECOG intergroup study comparing 6 to 8 cycles of CHOP versus R-CHOP in aggressive lymphoma was presented at the ASH 2003 annual meeting plenary session. This study enrolled 632 previously untreated patients 60 years of age, and complete responders underwent a second randomization to no maintenance therapy versus rituximab maintenance therapy every 6 months for 2 years (Habermann et al, 2006). Results from this trial, unlike the Groupe dEtude des Lymphomes de lAdulte (GELA) study, showed no difference in response rates or OS for the CHOP versus R-CHOP arms, although there was a benet in time to treatment failure for the R-CHOP arm at 2.7 years of median follow-up. The analysis was confounded to some extent by the secondary randomization to maintenance versus no-maintenance rituximab. Maintenance therapy was benecial for the time to treatment failure only in the CHOP-induction subset. As such, interpretation of these results supports the use of R-CHOP induction without subsequent maintenance rituximab therapy. Two other randomized controlled studies have been published supporting the benet of the addition of rituximab to anthracycline-based chemotherapy in DLBCL. The MabThera International Study Group (MINT) study included young (60 years) low-risk (IPI 0 or 1) patients with DLBCL who received either the investigators choice of anthracycline-based regimen versus the same regimen with rituximab. Most of the patients on this trial received standard CHOP (48%) or CHOP with etoposide (44%). The rituximab-containing regimens demonstrated an improvement in EFS and OS. Of interest, in a prior study by the German High-Grade NHL Study Group (DSHNHL), CHOP plus etoposide appeared to show an improvement in EFS in young patients with DLBCL compared with CHOP in a prior study (Pfreundschuh et al, 2004); however, with the addition of rituximab, this benet disappears, and as a result, rituximab has been referred to as the great equalizer (Pfreundschuh et al, 2006). The Rituximab With CHOP Over Age 60 Years (RICOVER) trial by the same group evaluated a CHOP-14 regimen (biweekly) with or without rituximab in elderly patients (60 years) and also demonstrated an improvement in all end points with the rituximab combination (Pfreundschuh et al, 2008). Of note, the latter study had a second randomization comparing 6 cycles to 8 cycles of chemotherapy and demonstrated that although patients
receiving 6 or 8 cycles of R-CHOP-14 had an improvement in EFS and PFS, only patients who had received 6 cycles had an improvement in OS, suggesting that this may be the optimal number of cycles. The interval reduction from 3 weeks (CHOP-21) to 2 weeks (CHOP-14) has been shown to improve the outcome of DLBCL in elderly patients without increasing toxicity (Pfreundschuh et al, 2004). In the largest randomized trial of DLBCL performed to date, the projected survival of elderly patients with DLBCL after 6 cycles of R-CHOP-14 was 74% at 2.5 years, which compares favorably with 64% in the GELA study. Trials are currently ongoing to determine whether reducing the cycle length of R-CHOP to 2 weeks results in improved outcomes compared with the standard 21-day cycle. A population-based retrospective analysis has also been reported from the British Columbia Cancer Agency (BCCA) comparing the outcomes of CHOP versus R-CHOP in patients with DLBCL (Sehn et al, 2005). Based on the results from the GELA study, R-CHOP was adopted as the standard of care in British Columbia in newly diagnosed patients 16 years of age with DLBCL in March 2001. The outcomes for patients treated in the 18-month period prior to (n 142) and after (n 152) the routine addition of rituximab to CHOP demonstrated highly statistically signicant differences in favor of R-CHOP for 2-year PFS (52% vs 71%; P .002) and OS (53% vs 77%; P .001). Importantly, both younger and older patients beneted from the addition of rituximab. As described earlier, the IPI was initially developed in approximately 4000 patients with large-cell lymphoma with diagnoses based on the Working Formulation. Thus, the majority of cases would be considered DLBCL by todays diagnostic criteria. A study of similar magnitude has not yet been performed in the postrituximab treatment era. However, limited studies suggest that the IPI is still prognostic of survival in DLBCL patients who have been treated with rituximab-containing regimens. The BCCA evaluated the IPI in R-CHOPtreated patients and demonstrated that 3 groups could be dened: very good risk (0 risk factors; 5-year PFS of 90%), good risk (2 risk factors; 5-year PFS of 70%), and poor risk (3 risk factors; 5-year PFS of 50%) (Sehn et al, 2007). The patient described earlier in the clinical case has an IPI score of 3 (age, stage, and LDH), placing her in a high-intermediaterisk group with an expected 5-year probability of survival of approximately 40% after therapy with CHOP or an equivalent regimen. However, with R-CHOP, the expectation is that the projected 5-year OS is approximately 55%. It has been proposed that patients in IPI poor-risk groups might benet from a more aggressive treatment approach, such as high-dose chemotherapy and ASCT or allogeneic stem cell transplantation. A recent European randomized trial in aggressive NHL patients tested 8 cycles of CHOP
versus 2 cycles of cyclophosphamide, epirubicin, vindesine, and prednisone followed by high-dose chemotherapy and ASCT and found higher 5-year EFS for patients in the transplantation arm. There was an OS benet for transplantation in the high-intermediate IPI risk subgroup. Whether these results would hold using R-CHOP as the standard chemotherapy arm versus HDT and stem cell transplantation is under study in a US intergroup trial of IPI high-intermediate- and high-risk patients (age-adjusted IPI score of 2 or 3) with aggressive NHL. Patients with bone marrow involvement by large-cell lymphoma and patients with sinonasal, paraspinal, or testicular involvement are at increased risk for CNS dissemination or relapse. However, there has been no denitive study that proves that there is a benet of CNS prophylaxis for such patients. The exception may be patients with sinus involvement, in whom intrathecal prophylaxis appears to have reduced the frequency of CNS disease. Despite this, intrathecal prophylaxis is often administered given the potential devastating consequence of secondary CNS disease, which is rarely curable. It appears that rituximab is reducing but not eliminating the risk of CNS relapse in DLBCL patients; thus, this complication still remains problematic in the postrituximab treatment era (Boehme et al, 2007; Villa et al, 2009).
Treatment of localized DLBCL
randomized controlled trial in localized DLBCL. The MINT study did include some patients with localized disease by nature of the inclusion criteria, but a large proportion also received radiotherapy to sites of bulky disease (5 cm). The SWOG recently published a phase II study evaluating 3 cycles of R-CHOP followed by IFRT (40-46 Gy if CR and 50-55 Gy if PR) in patients with localized (stage I, IE, nonbulky [10 cm] II or IIE) aggressive B-cell lymphoma, the majority of whom had DLBCL with at least 1 risk factor by the stage-modied IPI (Persky et al, 2008). The study population was similar to the prior SWOG study described earlier, and thus, a study to compare outcomes could be performed to determine the impact of the addition of rituximab to the combined-modality therapy. The 2-year PFS was superior in the R-CHOP patients (95% vs 83%). Although there has not been a randomized controlled trial, 3 cycles of R-CHOP followed by IFRT is considered the standard therapy for localized DLBCL.
Assessment of therapeutic response in DLBCL
Localized or limited-stage DLBCL usually includes patients with stage I and nonbulky (10 cm) stage II disease. Some groups or studies will also include patients with bulky stage I disease and exclude patients with B-symptoms. A large randomized trial established that 3 cycles of CHOP followed by IFRT is superior to 8 cycles of CHOP alone for the treatment of localized intermediate- and high-grade NHL (Miller et al, 1998). In this SWOG study, the 5-year OS for CHOP followed by radiotherapy was superior to that of CHOP alone (82% vs 72%), but a recent update with longer follow-up showed that the treatment advantage for the combinedmodality therapy was not sustained due to an excess of late relapses in the combined-modality arm, which was offset by increased toxicity in the chemotherapy alone arm. A stageadjusted IPI has been proposed for limited-staged disease that includes nonbulky stage II disease, advanced age (60 years), poor performance status (1), and elevated LDH as poor-risk factors. The 5-year OS rates reported in the updated follow-up for patients with 0, 1 or 2, and 3 risk factors were 94%, 71%, and 50%, respectively (Miller et al, 2003). The recently published GELA study did not reveal any added benet of consolidative radiotherapy after 4 cycles or CHOP chemotherapy for elderly patients with low-risk localized aggressive lymphoma (Bonnet et al, 2007). The benet of rituximab has not been specically analyzed in a
Assessment of response to therapy has varied among clinical studies and practitioners. A CT scan is usually performed after 4 cycles to assess response; patients will receive 2 additional cycles if in a CR, and patients with residual abnormalities after 4 cycles will often receive a total of 6 to 8 treatments, although the RICOVER study would suggest that 6 cycles is optimal. One of the difculties in assessing response is the inability to determine, even with repeat biopsy in some cases, whether residual lesions on CT scans represent brosis or lymphoma. PET scanning has been shown to be more sensitive than CT scan or gallium scan for both initial staging and assessment of response. As outlined earlier, several studies have suggested that the achievement of early PET negativity, after only 2 to 4 cycles of chemotherapy, strongly correlates with durable remission, whereas patients who remain PET positive have high rates of relapse or progression. Although PET scans are not mandatory in staging and assessment of response, given more widespread use in addition to use in clinical trials, the revised response criteria now include PET scan in the assessment of response to treatment (Cheson et al, 2007). If a PET scan is negative, a patient is considered to be in CR, even if a residual mass is present. In the past, such patients were considered as having either unconrmed CR or PR depending on the degree of tumor shrinkage. PET scans are strongly recommended in DLBCL patients before treatment but not absolutely required given limited availability. A pretreatment PET scan facilitates interpretation of the mid- or posttreatment response assessment. However, it is unknown whether patients with DLBCL who have a positive PET scan mid-treatment benet from a change of therapy, and this question is currently being tested in clinical trials. Given
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the possibility of false-positive PET scans, a biopsy should be performed if a change of therapy or high-dose chemotherapy or stem cell transplantation are under consideration.
Relapsed and refractory DLBCL
Patients with DLBCL that has relapsed after initial response should receive a second-line chemotherapy regimen such as ESHAP, ICE, DHAP, GDP, or EPOCH (see Table 18-9 for regimens) followed by HDT with autologous stem cell rescue if chemotherapy-sensitive disease is demonstrated. There are no randomized controlled trials conrming the efcacy of the addition of rituximab to any of these regimens, but it is often added given the strong data in the primary setting. Further phase II studies support that higher response rates are observed using rituximab in combination with chemotherapy. The use of HDT and ASCT in relapsed DLBCL is based on the PARMA study in which patients with relapsed aggressive lymphomathe majority of whom had DLBCL received 2 cycles of DHAP salvage chemotherapy; if a PR or a CR was attained, they were randomized to receive either further chemotherapy with DHAP or HDT (with carmustine, etoposide, cytarabine, and cyclophosphamide) and ASCT. The latter resulted in an improvement in the 5-year EFS (46% vs 12%; P .038; Philip et al, 1995). The optimal second-line therapy combination is unknown. The ongoing Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study is designed to compare rituximab plus DHAP with rituximab plus ICE as well as to study the role of maintenance rituximab in relapsed and refractory DLBCL (Gisselbrecht et al, 2007). An early report from this study at the ASH 2007 meeting suggests that patients who relapse following prior treatment with rituximab may have lower response rates and an inferior outcome compared with rituximab-naive patients. Patients with primary refractory lymphoma and those with chemotherapy-resistant disease have a very poor prognosis and should be considered for investigational regimens. The roles of allogeneic transplantation, 131I-tositumomab or 90Y-ibritumomab tiuxetan radiolabeled monoclonal antibodies, and novel biologic agents are currently under study in these settings. Primary mediastinal (thymic) large B-cell lymphoma PMBCL is a specic subtype of DLBCL that was distinguished based on unique clinicopathologic characteristics. Patients are typically females with a median age of 35 years who present with a bulky anterior mediastinal disease that can be locally invasive into the lung and chest wall occasionally with symptoms of superior vena cava syndrome. Distant spread, including bone marrow involvement, is uncommon at diagnosis.
Clinically, there are many similarities in presentation to CHL, in particular the nodular sclerosis subtype including predominant mediastinal disease. At relapse, involvement of unusual extranodal sites can occur in PMBCL, including the kidneys, adrenals, ovaries, liver, spleen, and CNS. Histologically, sclerosis is typically present, and phenotypically, the cells may lack surface immunoglobulin expression but express B-cell markers such as CD19 and CD20. CD30 is present in 30% of cases; however, it is usually weak and heterogeneous. Interestingly, recent gene expression analysis has shown that PMBCL is molecularly distinct from typical DLBCL and shares many components of the molecular signature with Hodgkin Reed-Sternberg cell lines (Savage et al, 2003; Rosenwald et al, 2003). There is also evidence of NF-B activation in PMBCL, similar to ndings in CHL (Feuerhake et al, 2005). Treatment of PMBCL is similar to DLBCL, with R-CHOP chemotherapy considered to be the standard therapy, and some centers in Europe use MACOP-B in addition to rituximab, but a direct comparison in a randomized trial has not been performed. IFRT is often administered to the mediastinum followed by chemotherapy, but it is unknown whether this reduces relapse rate in a patient otherwise in CR. The outcome of patients with PMBCL is excellent even in the prerituximab treatment era (5-year OS, 70%; Savage et al, 2006), and retrospective studies suggest that a similar magnitude of benet of rituximab that is seen in DLBCL is also achieved in PMBCL. The role of PET scanning to identify patients with residual disease at the bulky site (as opposed to brosis only) and who thus may be at increased risk for relapse and candidates for other therapeutic intervention, including radiotherapy, is currently under study. Burkitt lymphoma Burkitt lymphoma is among the most aggressive of all human malignancies, with a rapid doubling time, acute onset, and progression of symptoms. Originally described in its endemic form in African children presenting with jaw or facial masses, it also occurs in sporadic form in the Western world, predominantly in children and young adults. It is also seen in HIV-infected patients. Most endemic and some sporadic cases show evidence of EBV infection and presence of the EBV genome. Clinically, most patients with Burkitt lymphoma present with a bulky abdominal mass, B-symptoms, and frequent extranodal and bone marrow involvement (up to 70%; Perkins et al, 2008). CNS dissemination, usually in the form of leptomeningeal involvement, may be present at diagnosis in up to 40% of patients; as a result, high-dose methotrexate and intrathecal chemoprophylaxis are integrated into the therapy for all Burkitt lymphoma patients.
Histologically, Burkitt lymphoma has a diffuse growth pattern of medium-sized cells and a high mitotic rate, as depicted by nearly 100% of cells showing positivity for Ki-67 due to deregulated high-level expression of c-MYC arising from reciprocal translocation with immunoglobulin heavy (t8;14) or light chain gene loci (t8;2 or t8;22). There is also a high rate of cell death or apoptosis, and the dead cells are phagocytosed by histiocytes, which gives a starry sky appearance at low power. The B cells are positive for CD19, CD20, and CD10. BCL2 is usually negative, but in the updated WHO classication, weakly positive cases (20%) can be included. Lack of TdT is critical to rule out acute lymphoblastic leukemia/lymphoma. Recent gene expression proling studies show that Burkitt lymphoma has a distinct molecular signature distinguishing it from DLBCL (Hummel et al, 2006; Dave et al, 2006). Therapy for Burkitt lymphoma must be instituted quickly due to the rapid clinical progression of the disease. Admission to hospital and tumor lysis precautions are essential and include vigorous alkalinization, hydration, allopurinol, and close monitoring of laboratory studies including electrolytes and renal function. Early dialysis is indicated at the rst signs of decreasing renal function, hyperkalemia, and/ or hyperphosphatemia. Recently, recombinant uric acid oxidase (rasburicase) has been shown to be very effective in preventing uric acid nephropathy and its secondary metabolic complications. CHOP chemotherapy is inadequate for the treatment of Burkitt lymphoma. Multiagent combination chemotherapy that includes high doses of alkylating agents and CNS prophylaxis have improved the outcome for adults and children with the disease. The most commonly used approaches today include intensive short-duration chemotherapy, acute lymphoblastic leukemiatype chemotherapy, and intensive chemotherapy followed by high-dose chemotherapy and ASCT. Given disease rarity, there are no randomized controlled treatment trials in adults comparing these approaches. Magrath et al (1996) at the National Cancer Institute demonstrated a risk-adapted strategy that is useful for treatment stratication in both adults and children. Low-risk patients were those with a single extra-abdominal mass or completely resected abdominal disease and a normal LDH, and all other patients were considered high risk. Lowrisk patients received 3 cycles of cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M) only, and high-risk patients received CODOX-M alternating with ifosfamide, etoposide, and cytarabine (IVAC) for a total of 4 cycles (ie, 2 cycles each of CODOX-M and IVAC). All patients received intrathecal chemoprophylaxis with each cycle, and those with CNS disease at presentation received additional intrathecal therapy during the rst 2 cycles. Approximately half of the patients were adults, and the 2-year EFS for all patients was 92%. Of note, some of the patients in this study
had what has been previously referred to as Burkitt-like lymphoma, and the median age of adult patients was still only 24 years. Two other phase II studies have used the Magrath regimen with minor modications. In a United Kingdom study, adult (age range, 16-60 years; median, 26.5 years), nonHIV patients were treated with dose-modied CODOX-M (3 g/m2) for 3 cycles if determined to be low risk (ie, normal LDH, performance status of 0 or 1, Ann Arbor stage I or II, and no tumor mass 10 cm), and all other patients were considered high risk and treated with alternating dosemodied CODOX-M/IVAC. The 2-year PFS for the patients with Burkitt lymphoma was 64%. At the Dana-Farber Cancer Institute, an older population (median age, 47 years) of patients was studied (n 14), and the reported 2-year EFS was 71% with a modied Magrath regimen (Lacasce et al, 2004). Other therapeutic approaches have included the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD)/methotrexatecytarabine regimen and acute lymphoblastic leukemiatype regimens. Of note, in the modern treatment era, there is no role for radiotherapy in the treatment of Burkitt lymphoma, even for localized disease. The role of consolidative ASCT in Burkitt lymphoma is unknown. Given the limited data in older patients, the results from 12 large treatment series (10 prospective and 2 retrospective) were combined to better determine outcome in patients with Burkitt lymphoma in patients 40 years of age (Friedberg et al, 2005). In total, 470 patients were identied, 183 of whom were 40 years. The median OS at 2 years with intensive short-duration chemotherapy was inferior compared with patients 40 years (39% vs 71%). Patients in the older age group who underwent ASCT appeared to have a more favorable prognosis (median OS at 2 years, 62%), but this was a small group, and selection bias may have been introduced. Mantle cell lymphoma In many ways, MCL falls between the indolent and aggressive lymphomas, unfortunately combining the poorer attributes of each, namely the lack of curability with standard therapy typical of the indolent subtypes and a relatively aggressive clinical course with median survival historically of 3 to 4 years. However, in recent years with more dose-intensive regimens including stem cell support, the median survival may be shifting to 5 years or more (Geisler et al, 2007). The clinical features of MCL include median age of 60, a striking male predominance, advanced stage at presentation frequently with bone marrow and peripheral blood involvement, and splenomegaly. Extranodal involvement is present in the majority of cases, with a peculiar tendency to invade the gastrointestinal (GI) tract, which may present as a distinctive
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syndrome of multiple lymphomatous polyposis of the large bowel. Even patients without overt colonic polyposis frequently have subclinical GI epithelial invasion by biopsy. Other extranodal sites may include the Waldeyer ring, lungs, kidneys, prostate, or CNS. Hypogammaglobulinemia is not uncommon, and IgM monoclonal gammopathy may occur in approximately 25% of the patients. Cytologically, the majority of MCLs consist of small lymphocytes with notched nuclei. The architectural pattern of the lymph node is usually diffuse but may show a vaguely nodular or mantle zone growth pattern. A spectrum of morphologic variants has been recognized, including small cell, mimicking SLL/CLL, and marginal zone, which has been associated with a more indolent course. The aggressive variants are blastoid, which has a high mitotic rate, and pleomorphic. The immunophenotype of MCL is that of a B-cell lymphoma, and in addition, they are typically CD5, FMC, and CD43 but CD10 (Table 18-2). Some of the salient features that distinguish MCL from SLL or CLL are the expression in MCL of cyclin D1 and FMC-7 and the lack of CD23 expression (Table 18-2). Furthermore, MCL has a more intense or bright surface IgM and/or IgD and CD20 expression than SLL and CLL. Virtually all MCLs carry the t(11;14) (q13;q32) on karyotypic analysis or by uorescence in situ hybridization technique. This reciprocal translocation juxtaposes the immunoglobulin heavy chain locus and the cyclin D1 (CCND1) gene. cDNA microarray analysis has demonstrated that genes associated with cellular proliferation show striking variability among MCL cases, ranging from low to very high expression. Patients in the lowest quartile of expression have median survival times of 6 to 8 years, whereas patients in the highest expression quartile have survivals of 1 year (Rosenwald et al, 2003). MCL is chemotherapy sensitive, but response duration is typically short with standard chemotherapy such as chlorambucil, CVP or CHOP, or nucleoside analogs. There is no evidence of superiority of anthracycline-based chemotherapy in the treatment of MCL; however, given a higher ORR, CHOP or other more intensive regimens are often used as the backbone of therapy. The benet of rituximab is less established in MCL compared with DLBCL. The German Low Grade Lymphoma Study Group (GLSG) compared CHOP with R-CHOP in untreated advanced-stage MCL, with a second randomization in responding patients to ASCT or interferon alfa maintenance therapy. R-CHOP had superior ORR (94% vs 75%), CR rate (34% vs 7%), and time to treatment failure; however, the PFS and OS were equivalent in the 2 arms. In the relapsed setting, rituximab plus FCM (R-FCM) was compared with FCM in patients with follicular lymphoma and MCL, with a second randomization to observation versus rituximab maintenance. In the rst randomization, the trial was stopped because R-FCM was shown to
be superior to FCM at reducing the risk of relapse, and all subsequent patients received R-FCM. Response duration was prolonged in MCL patients receiving maintenance rituximab (P .049); however, the median duration of response was similar, and the estimated 3-year OS was not statistically signicant (77% vs 57%; P .11) (Forstpointner et al, 2006). Rituximab has also been evaluated at a single institution with HyperCVAD alternating with rituximab plus high-dose methotrexate and cytarabine with reported high ORR and encouraging PFS at 2 years of 60% (Romaguera et al, 2005); however, these results have not been replicated in a subsequent multicenter trial. Given the poor results with standard chemotherapy, autologous transplantation has been explored in the hope of prolonging response duration and possible cure. A matchedpair analysis comparing standard chemotherapy with up-front ASCT plus rituximab in vivo purging showed a superior PFS at 3 years (89% vs 29%; P .00001) and a trend toward improved OS in patients receiving the high-dose approach (Mangel et al, 2004). The Nordic group evaluated intensive induction immunochemotherapy with alternating cycles of maxi R-CHOP and rituximab plus cytarabine followed by in vivo purge (with rituximab) and ASCT in a phase II trial. The ORR was 96%, and the 6-year EFS and OS were 56% and 70%, respectively, with no relapses observed after 5 years; however, follow-up is still short, and it is too early to determine whether this represents a curative approach (Geisler et al, 2007). Allogeneic stem cell transplantation still remains the only known curative therapeutic option in MCL but is not applicable to the majority of MCL patients, who are generally of older age. Other investigational approaches include nonmyeloablative stem cell transplantation, reported by Khouri et al (2003) to have a high and durable response rate with acceptable toxicity in 18 patients, most with chemotherapy-sensitive disease. Bendamustine in combination with rituximab has been tested in relapsed MCL and is highly active, with an ORR of approximately 90% and a median duration of response of 19 to 24 months. As described earlier, rst-line therapy with bendamustine plus rituximab is being compared with R-CHOP in indolent lymphomas and MCL and appears to be equivalent. Bortezomib has moderate activity in MCL, with an ORR of 45% in MCL patients, but the time to progression is only 6 months. Thalidomide in combination with rituximab had a high ORR (81%) in a small phase II trial, and lenalidomide is also highly active in relapsed MCL. Cyclin D1inhibitory agents such as avopiridol and temsirolimus are under evaluation in MCL. Radioimmunotherapy has been evaluated in MCL, with an ORR of 30% to 40%, but remission duration is disappointingly short. Overall, young patients should be treated aggressively with R-CHOP or similar induction followed by
ASCT or with up-front dose-intensication rituximab plus HyperCVAD. Older patients can be treated with a variety of regimens depending on additional comorbidities including R-CHOP, R-CVP, or udarabine-containing regimens. Peripheral T-cell lymphomas Peripheral T-cell lymphomas (PTCLs) represent 12% of all NHLs in Western populations and are a heterogenous group of mature T-cell neoplasms arising from postthymic T cells at various stages of differentiation. NK-cell lymphomas are included in this group because of the close relationship between these 2 cell types. The importance of the T-cell phenotype and impact on prognosis is now well established but is a relatively recent advance. Progress in elucidating the pathobiology and appropriate therapy of these neoplasms has been slow, primarily due to their rarity but also because until the early 1990s, they were generally grouped together and combined with B-cell lymphomas. It is now understood that the majority of PTCLs are highly aggressive, respond poorly to standard chemotherapy, and thus have a signicantly poorer prognosis than their B-cell counterparts. A recent large retrospective study, the International Peripheral T-Cell Lymphoma Project (ITLP), collected 1153 cases of PTCLs from 22 centers from around the world and highlighted the geographic, clinicopathologic, and prognostic differences of this diverse group of diseases (Vose et al, 2008). The most common subtypes encountered in North America are PTCLnot otherwise specied (PTCL-NOS), AITL, and ALCL. Given disease rarity, there are no randomized controlled trials establishing that an alternate regimen is superior to CHOP, and thus CHOP remains the standard therapy of PTCLs. However, there is a range of disease in this category (Table 18-4), and a minority have a more favorable prognosis or a more indolent course.
Indolent PTCLs Mycosis fungoides and Szary syndrome
Mycosis fungoides (MF) is an epidermotropic, primary cutaneous T-cell lymphoma and represents the most common of all primary cutaneous lymphomas (50%). Most cases occur in adults, and there is a male predominance. The disease is limited to the skin in its early phases and appears as plaques or patches, but with time, it evolves to diffuse erythroderma or cutaneous nodules or tumors, usually with associated adenopathy. Extracutaneous disease can occur in advanced stages and may indicate histologic transformation. MF has an indolent clinical course with slow progression from patches to plaques and tumors over years and remains incurable. The overall 5-year disease-specic survival is approximately 90% (Willemze et al, 2005). The histology varies with stage of the
disease, but typical epidermotropism is seen with typical plaques and intradermal collections of so-called Pautrier microabscesses. Immunophenotypic analysis reveals T-cell markers, typically with a CD4/CD8 (T-helper) phenotype. Progression to nodal disease, organ inltration, and circulating clonal T cells (Szary syndrome) represents the advanced stage of disease. Often early-stage disease is misdiagnosed as psoriasis or another chronic skin condition, at times for several years, prior to biopsy and recognition of its true nature. A unique clinical staging system has been proposed by the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC) for MF and Szary syndrome (Olsen et al, 2007). The extent of cutaneous and extracutaneous disease is the most important prognostic factor in MF, with a 10-year disease-specic survival ranging from 97% to 98% for patients with limited patch/plaque disease (10% of skin surface; stage I) to 20% for patients for patients with lymph node involvement. Szary syndrome is a distinct disorder characterized by erythroderma, generalized lymphadenopathy, and the presence of Szary cells in the skin, lymph nodes, and peripheral blood. One of the following is also required: Szary cell count 1000/L; CD4/CD8 ratio of 10 resulting from an expanded CD4 population; or loss of 1 T-cell antigen (CD2, CD3, CD4, or CD5) (Swerdlow et al, 2008). Szary syndrome is much rarer than MF, and patients often have intense pruritus, alopecia, and hyperkeratosis on the palmar and plantar surfaces. It also is associated with a more aggressive course, with a 5-year OS rate of 20% to 30%. The prognosis is more favorable with Szary cell counts of 1000 Szary cells/L (7.6 years) versus 10,000 Szary cells/L (2.4 years). For MF, control of the cutaneous phase may be accomplished by topical nitrogen mustard, electron-beam radiotherapy, or cutaneous photochemotherapy with oral psoralen plus ultraviolet A (PUVA). Patients with progressive disease and those with systemic dissemination may be palliated with methotrexate and/or corticosteroids, although responses are usually poor and transient. Combination chemotherapy regimens are not particularly effective and provide only transient responses (Prince et al, 2009). Interferon alfa, bexarotene, vorinostat, and denileukin diftitox all have efcacy in advanced-stage MF and Szary syndrome. Denileukin diftitox is a recombinant fusion protein that combines interleukin 2 (IL-2) with the cytotoxic A chain of diphtheria toxin with an ORR of 49%. It has recently been approved by the US Food and Drug Administration (FDA) for patients with relapsed cutaneous T-cell lymphoma whose tumors express the IL-2 receptor subunit (CD25). The FDA has also recently approved suberoylanilide hydroxamic acid (SAHA; vorinostat) for the treatment of cutaneous T-cell lymphoma, which is an
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orally available hydroxamic acid with an ORR of 24%. A number of chemotherapy agents have activity in MF and Szary syndrome. Single-agent treatment is preferred, particularly with slowly progressive disease, due to a high risk of myelosuppression and infection and only modest response durations seen with combination chemotherapy. Gemcitabine, pentostatin, and liposomal doxorubicin have good single-agent activity. Alemtuzumab, the humanized monoclonal antibody targeting CD52, has also been used in MF and Szary syndrome with some success; however, patients are at high risk of opportunistic infections.
Primary cutaneous ALCL
nding, and lymphadenopathy is rare. Severe neutropenia with or without anemia is common, but thrombocytopenia is rare. Red blood cell aplasia may also occur. The immunophenotype is CD3 and CD8, with clonality demonstrated by TCR gene rearrangement studies. CD57 and CD16 are expressed in 80% of cases. If treatment is required for cytopenias, cyclosporine A, chlorambucil, cyclophosphamide, or corticosteroids can be effective. Splenectomy may also be useful in cases with an accompanying splenomegaly and or cytopenias (Mohan and Maciejewski, 2009). The antiCD52 monoclonal antibody alemtuzumab has been reported to be effective (Rosenblum et al, 2004).
Aggressive PTCLs Adult T-cell leukemia/lymphoma
Primary cutaneous ALCL (C-ALCL) is part of a spectrum of diseases in the category of primary cutaneous CD30 T-cell lymphoproliferative disorders that also includes the lymphomatoid papulosis and borderline cases that have overlapping features of both disorders. C-ALCL must be distinguished from systemic ALCL with secondary cutaneous involvement through staging procedures. Patients with C-ALCL typically present with a solitary nodule and have a favorable outcome, with a 10-year disease-specic survival of 90%. For localized disease, surgery with or without radiation is the preferred therapy, and the impact of chemotherapy is unknown. Progression to systemic involvement can occur in a minority of cases.
Primary cutaneous CD4 small/medium T-cell lymphoma
This is a new provisional entity in the updated WHO classication and is characterized by the presence of localized plaques or nodular lesions that most commonly occur on the face, neck, or upper trunk. Epidermotropism is uncommon and, if present, is focal. The malignant cells are CD3, CD4, and CD8 and may be accompanied by a loss of pan-T-cell markers. The prognosis is excellent, with a 5-year OS of 80%. Localized lesions are typically treated with surgery with or without radiotherapy.
T-cell large granular lymphocytic leukemia
T-cell large granular lymphocytic leukemia is dened by a persistent (6 months) increase in the number of peripheral blood large granular lymphocyte cells without an identiable cause. Concurrent rheumatoid arthritis can also occur. Most cases have an indolent clinical course, with a median survival time of approximately 13 years, but rare cases with an aggressive course have also been described. Of note, T-cell large granular lymphocytic leukemia should be distinguished from NK-cell leukemia, which does have a fulminant aggressive course (see following Aggressive NK-cell leukemia section). In T-cell large granular lymphocytic leukemia, moderate splenomegaly is the most common clinical
Adult T-cell lymphoma/leukemia is caused by infection with HTLV-1 and occurs in endemic areas of infection (eg, Caribbean basin and southwestern Japan). HTLV-1 alone is not sufcient to result in neoplastic transformation, and the cumulative incidence of adult T-cell lymphoma/leukemia among HTLV-1 carriers is 2.5% in Japan. The virus can be transmitted in breast milk and through exposure to blood products. Pathologically, the malignant cells have a distinct cloverleaf appearance and lack CD7, and the majority are CD4/CD8. The following clinical variants have been recognized: acute type with a rapidly progressive clinical course, bone marrow and peripheral blood involvement, hypercalcemia with or without lytic bone lesions, skin rash, generalized lymphadenopathy, hepatosplenomegaly, and pulmonary inltrates; lymphoma type with prominent adenopathy but lacking peripheral blood involvement but also associated with an aggressive course; chronic type with lymphocytosis and occasionally associated with lymphadenopathy, hepatosplenomegaly, and cutaneous lesions but having an indolent course; and smoldering type with 5% circulating neoplastic cells, skin involvement, and prolonged survival. Survival time in the acute and lymphomatous variants ranges from 2 weeks to 1 year. The chronic and smoldering subtypes have a longer survival but can transform into the more acute forms. Underlying immunodeciency associated with adult T-cell lymphoma/leukemia leads to a high rate of infections throughout the disease course.
Aggressive NK-cell leukemia
This is a rare form of leukemia that is almost always associated with EBV infection and an aggressive course, with a median survival of 3 months. It is seen more often in Asians, and the median age of onset is 42 years. Typically, the bone marrow and peripheral blood are involved in addition to the liver and spleen. Patients often have fever and constitutional symptoms and multiorgan failure with coagulopathy and
hemophagocytic syndrome. It is unclear whether aggressive NK-cell leukemia represents the leukemic phase of extranodal NK/T-cell lymphoma. There is no known curative therapy, and responses to chemotherapy are usually brief. Some encouraging results have been seen with L-asparaginase based treatment in this disease and extranodal NK/T-cell lymphoma but require further study.
PTCLnot otherwise specied
AITL are mature CD4/CD8 T cells, expressing most panT-cell antigens. In recent years, a number of studies support that the follicular helper T cell is the normal physiologic cell counterpart of AITL. Consistent with this, the tumor cells are CD10, BCL6, and CXCL13 positive. A follicular helper T-cell derivation is also supported by recent gene expression proling (de Leval et al, 2007). EBV is identied in most cases in the surrounding B cells.
Anaplastic large-cell lymphoma
PTCL-NOS is the most common subgroup of PTCLs, accounting for up to 30% of cases worldwide. This is the default PTCL category for any mature T-cell neoplasm that does not t into any of the specied categories in the WHO classication. Patients typically present with advanced-stage disease, and the 5-year survival is 20% to 30% in most series. Recognizing that the division of PTCLs into leukemic, nodal, and extranodal is somewhat articial, these categories have been eliminated in the updated WHO classication (Table 18-4). The morphologic spectrum of PTCL-NOS is wide, including the histiocyte-rich lymphoepithelioid or Lennert lymphoma. Typically, the neoplastic cells are T-helper (CD4/CD8) phenotype; CD5 and CD7 are frequently downregulated, and approximately 30% are CD30. CHOP chemotherapy is considered the standard of care in PTCLNOS, but it is largely ineffective. Consolidative therapy with HDT and ASCT is being explored with conicting results in phase II studies and is still considered experimental. Gene expression proling has been explored in heterogeneous PTCL-NOS to determine whether there are reproducible, molecular subsets and to better dene prognostic markers within PTCL-NOS. However, in comparison to B-cell lymphomas, large-scale studies are lacking. A recent study evaluating 35 cases of nodal PTCL-NOS found that high expression of proliferation-associated genes was associated with a worse prognosis (Cuadros et al, 2007). Another study by the same Spanish group found that expression of NF-B pathway genes was associated with a more favorable prognosis in PTCL-NOS (Martinez-Delgado et al, 2005).
Angioimmunoblastic T-cell lymphoma
ALCL was originally described as a lymphoma composed of large anaplastic lymphoid cells, uniformly strongly positive for CD30 and with a predilection for a sinusoidal and cohesive growth pattern (Stein et al, 1985). Since then, there has been signicant progress made in further classifying this subgroup of PTCLs. It includes cases that have T-cell or nullcell lineage, the latter implying loss of T-cell antigens but monoclonality demonstrable. B-cell cases are considered a subtype of DLBCL. In the WHO classication, primary systemic ALCL is separated from primary cutaneous ALCL, and more recently, ALK-positive ALCL has been dened a distinct entity in the updated classication (Table 18-4). Cases of ALK-positive ALCL are associated with a characteristic chromosomal translocation, t(2;5)(p23;q35), resulting in a fusion gene, NPM-ALK, encoding a chimeric protein. With the availability of antibodies to the ALK protein, ALK expression can be demonstrated in 60% to 85% of all systemic ALCL, with higher frequencies seen in the pediatric and young adult age groups. In contrast, although ALK-negative ALCL lacks any dening features, there is accumulating evidence that it should be separated from other PTCLs; as a result, it is considered a provisional entity in the updated WHO classication.
ALK-positive ALCL
AITL is a well-dened, distinct PTCL subtype, with unique pathobiologic features. Similar to PTCL-NOS, patients are typically older and have advanced-stage disease, often with B-symptoms and hepatosplenomegaly. It was originally believed to be a form of immune dysregulation, with polyclonal gammopathy being a common nding. Survival is similar to PTCL-NOS; however, a small proportion may have a more indolent course. Key morphologic ndings of AITL include an expanded CD21 follicular dendritic cell network and prominent arborizing high endothelial venules. The neoplastic cells in
Morphologically, ALK-positive ALCL has a spectrum of appearances, and all subtypes have a variable proportion of the pathognomonic hallmark cells recognized by their eccentric, horseshoe, or kidney-shaped nuclei. In addition to strong expression of CD30, ALK-positive ALCL is usually positive for epithelial membrane antigen (EMA) and cytotoxic markers (TIA1, granzyme B, and perforin). Several studies have now rmly established that patients with ALKpositive ALCL have a much more favorable prognosis with anthracycline-based chemotherapy than patients who have ALK-negative ALCL and other PTCLs, as well as DLBCL, at least in the prerituximab treatment era (Gascoyne et al, 1999). The improved outcome may in part be related to the young age at presentation. As indicated earlier, ALK-positive ALCL has a characteristic genetic rearrangement forming a fusion gene that encodes for the 80-kd NPM-ALK chimeric
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protein, which possesses signicant oncogenic potential resulting from constitutive activation of the tyrosine kinase ALK.
ALK-negative ALCL
In the fourth edition of the WHO classication, ALKnegative ALCL is considered a provisional entity, distinct from both ALK-positive ALCL and PTCL-NOS. Patients with ALK-negative ALCL tend to be older at presentation; otherwise, the clinical presentation is similar to ALK-positive cases, although sites of extranodal disease may vary. ALKnegative ALCL has been difcult to dene, in part due to a lack of uniformly applied diagnostic criteria across studies. Moreover, a specic oncogenic abnormality comparable to the ALK gene rearrangement has not been identied. Like ALK-positive ALCL, ALK-negative ALCL is composed of large lymphoid cells that are strongly positive for CD30 with abundant cytoplasm. It is not reproducibly distinguished from ALK-positive ALCL other than lacking the ALK protein. The prognosis of ALK-negative ALCL is poor, but there is some recent evidence that it may be more favorable than PTCL-NOS (Savage et al, 2008).
Extranodal NK/T-cell lymphoma, nasal-type
typically has a CD4, CD8, and CD5 phenotype and is rarely associated with hemophagocytic syndrome, which is associated with a worse prognosis. The updated WHO species that SCPTCL should be restricted to cases with the - phenotype. The - subtype has been combined in the new WHO classication with a new, rare PTCL entity, termed primary cutaneous - T-cell lymphoma (see later section) due to similar aggressive behavior (Table 18-4). Durable responses have been observed with both CHOP and immunosuppressive agents.
Hepatosplenic T-cell lymphoma
Extranodal NK/T-cell lymphomas, nasal-type, display great variation in racial and geographic distribution, with the majority of cases occurring in the East Asia. The designation NK/T is used to reect the fact that, although most are NK-cell derived [CD2, CD56, CD3(cytoplasmic), EBV], rare cases with identical clinical and cytologic features exhibit an EBV/ CD56 cytotoxic T-cell phenotype. The qualier nasal-type is used because although most cases present in the nasal region and associated structures, identical tumors can also occur at extranasal sites, such as the skin, soft tissue, GI tract, and testis. From the International T-Cell Lymphoma Project and other studies, it appears that cases that occur in extranasal regions may have a more aggressive course (Au et al, 2009). Accumulating evidence supports that radiotherapy is the most important treatment modality for localized disease. Alternate chemotherapy combinations in extranodal NK/T-cell lymphomas, nasal-type, including asparaginase and methotrexate, have shown encouraging results but await further study (Jaccard et al, 2009).
Rare PTCL subtypes Subcutaneous panniculitis-like T-cell lymphoma
Hepatosplenic T-cell lymphoma is a recently recognized and uncommon PTCL subtype. The majority of patients are young men (median age, 34 years) presenting with hepatosplenomegaly and bone marrow involvement. Up to 20% of hepatosplenic T-cell lymphomas occur in the setting of immunosuppression, most commonly following solid organ transplantation (WHO). It has also been observed in patients treated with azathioprine and iniximab for Crohn disease. The splenic red pulp is diffusely involved, and the liver will show a sinusoidal pattern. Most tumor cells are CD3, CD4, and CD8, and most are associated with isochrome 7q. The majority of cases are of the - TCR type; however, rare cases that are of the - TCR type have been reported. The prognosis is extremely poor with rare long-term survivors. The optimal therapy is unknown; however, some long-term survivors have been reported with high-dose chemotherapy and ASCT or allogeneic stem cell transplantation.
Enteropathy-associated T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL) is an extremely uncommon PTCL subtype that preferentially inltrates the subcutaneous tissue. Recently, it has been determined that tumors with - phenotype have a far inferior prognosis to those with - phenotype (5-year OS, 11% for - vs 82% for -). The more common - SCPTCL
Enteropathy-associated T-cell lymphoma is a rare, aggressive intestinal tumor with a male predominance and occurs in the setting of celiac disease. It most commonly involves the jejunum or ileum. Patients often present with abdominal pain, and intestinal perforation can occur. The prognosis is extremely poor due to chemotherapy resistance and difcult treatment delivery related to abdominal complications that can arise in the setting of malabsorption. In some cases, there is a childhood history of celiac disease, but more commonly, the disease occurs in adulthood. Alternatively, there is a prodrome of refractory disease, or a concomitant diagnosis of celiac disease is found at the time the lymphoma is discovered. In the updated WHO classication, a sporadic, monomorphic variant, type II enteropathy-associated T-cell lymphoma, is more clearly dened that occurs in 10% to 20% of cases and has a broader geographic distribution that includes Asia. An association with celiac disease has not been denitively proven in this subtype; thus, this may represent a distinct disease entity. In the common subtype, the neoplastic cells are CD3, CD7, CD4, CD8/, and CD56 and contain cytotoxic proteins.
Immunodeciency-associated lymphoproliferative disorders | 539
Primary cutaneous PTCL, rare aggressive subtypes Primary cutaneous - T-cell lymphoma
In the updated WHO classication, primary cutaneous - T-cell lymphoma is now considered a distinct entity, which also includes cases previously known as SCPTCL with a - phenotype, as described earlier. Clinically, the extremities are commonly affected, and the presentation can be variable, with patch/plaque disease or subcutaneous and deep dermal tumors that may exhibit necrosis and ulceration. The clonal T cells have an activated - cytotoxic phenotype, with most cases being negative for both CD4 and CD8 and positive for TCR-. Prognosis is poor in this disease, particularly with subcutaneous fat involvement, with a fulminant clinical course and primary resistance to combination chemotherapy.
Primary cutaneous aggressive epidermotropic CD8 T-cell lymphoma
This provisional entity typically presents with generalized cutaneous lesions appearing as eruptive papules, nodules, and tumors with central ulceration and necrosis. Histologically, there is marked epidermotropism, and invasion into the dermis and adnexal structures is common. The tumor cells are CD3, CD4, CD8, and cytotoxic marker positive, and the clinical course is aggressive.
Immunodeciency-associated lymphoproliferative disorders

Congenital or acquired immunodeciency states are associated with an increased incidence of lymphoproliferative disorders. The WHO classication identies 4 such categories: (i) primary immunodeciency disorders including WiskottAldrich syndrome, ataxia-telangiectasia, common variable or severe combined immunodeciency, X-linked lymphoproliferative disorder, Nijmegen breakage syndrome, hyperIgM syndrome, and autoimmune lymphoproliferative syndrome; (ii) HIV infection; (iii) post solid organ or marrow transplantation with iatrogenic immunosuppression; and (iv) methotrexate- or other iatrogenic-related immunosuppression for autoimmune disease. The lymphomas seen in these settings are heterogeneous and may include HL or, more commonly, aggressive NHL. Chdiak-Higashi syndrome has also been associated with an increased incidence of pseudolymphoma and true NHL. Lymphoproliferative disorders associated with primary immune deciencies (PIDs) are most commonly seen in pediatric patients and are frequently associated with EBV infection. Extranodal disease including the CNS is common. Lymphomas occurring in patients with PID do not differ morphologically compared with immunocompetent hosts. DLBCL is the most frequent histologic type, although T-cell
lymphomas are more common in ataxia-telangiectasia. EBVrelated lymphomatoid granulomatosis is associated with Wiskott-Aldrich syndrome. These malignancies respond poorly to standard therapy. Therapy depends on both the underlying disorder and the specic lymphoma subtype; allogeneic transplantation has been used successfully in some patients. Novel immunotherapeutic or pharmacologic strategies targeting EBV are being explored (Heslop, 2005). HIV-associated lymphomas are typically monoclonal B-cell aggressive subtypes, usually DLBCL or Burkitt lymphoma. Approximately two thirds of cases are EBV associated, and many carry c-MYC oncogene translocations. CNS involvement is frequent. The entity of primary effusion lymphoma (body cavity lymphoma) usually presents in HIV-positive patients as ascites or a pleural effusion but may involve soft tissue or visceral masses. It is pathogenetically associated with HHV-8 (KSHV) and generally carries a poor prognosis. HL also occurs in the HIV setting but with much lower incidence and is usually the mixed cellularity of lymphocyte-depleted subtypes. Therapy for HIV-associated lymphomas has used both full-dose and dose-modied combination chemotherapy regimens, usually with cytokine support with granulocyte colony-stimulating factor (G-CSF) or GM-CSF and erythropoietin, and can lead to durable remissions. Appropriate HIV management such as highly active antiretroviral therapy (HAART) is essential and should be given concurrently with chemotherapy and in communication with the HIV specialist to avoid antiretrovirals that can exacerbate chemotherapy toxicity. Several registries have reported a signicant decline in the incidence of HIVassociated lymphoma since the introduction of HAART. The role of rituximab with anthracycline combinations in HIVassociated DLBCL is unknown, with one small randomized study showing no improvement in outcome relating to an increase in treatment-related infectious deaths. The toxicity was higher in patients with a CD4 count 50 (Kaplan et al, 2005). This is in contrast to a phase II French study of R-CHOP in aggressive lymphomas that demonstrated a 2-year OS of 75% without an increase in life-threatening infections, which likely reects the exclusion of poor-prognosis patients with a CD4 cell count of 100 or a performance status 2 (Boue et al, 2006). Thus, R-CHOP can be considered in HIV patients if the CD4 count is 50; however, it should be given in conjunction with G-CSF given the high rate of infection in this population. Posttransplantation lymphoproliferative disorders (PTLDs) occur as a consequence of immunosuppression in recipients of solid organ, bone marrow, or stem cell allograft. PTLDs are comprised of a spectrum of disorders ranging from EBV-positive infectious mononucleosis (early lesions) to polymorphic PTLD to full blown monomorphic PTLD that can be either EBV positive (common) or EBV negative and
540 | Lymphomas
are indistinguishable from B-cell lymphomas (common) and T-cell lymphomas (rare) that occur in immunocompetent hosts. HL-type PTLDs can also occur; however, indolent B-cell lymphomas arising in transplantation recipients are not among the PTLDs. Aggressive lymphomas occur in approximately 2% to 5% of patients after solid organ or marrow and stem cell transplantation. The risk of lymphoma is directly correlated with the degree of immunosuppression. These PTLDs may arise within the rst 6 months of transplantation or have a later onset beyond 1 to 2 years; the former is more commonly associated with EBV. More than 90% of PTCLs in solid organ recipients are of host origin; however, in contrast, most PTLDs in bone marrow allograft recipients are of donor origin. Although a minority of patients will respond to a reduction in intensity of immunosuppression, particularly in polymorphic PTCL, most require additional systemic therapy. The prognosis for such patients has been poor due to both inadequate response and poor tolerance of chemotherapy. Single-agent rituximab in PTLD has demonstrated an ORR of approximately 40% to 75% and is extremely well tolerated (Svoboda et al, 2006); however, remission duration may be short in many patients. In one large phase II prospective study of 60 patients treated with single-agent rituximab, the median PFS was only 6 months; however, the 1- and 2-year OS rates were 72.5% and 51.8%, respectively, suggesting that these patients could be salvaged with either chemotherapy or re-treatment with rituximab (Choquet et al, 2006). Another approach is the infusion of graded doses of EBV-specic cytotoxic lymphocytes. Durable CR rates of up to 80% have been reported with this therapy. Primary CNS lymphoma Primary CNS lymphoma (PCNSL) is distinguished in the updated WHO classication as DLBCL subtype. Most intraparenchymal lymphomas show a diffuse growth pattern typically in the perivascular space. In addition to B-cell markers, CD10 expression is observed in 10% to 20%, and BCL6 expression is common (60% to 80%). PCNSLs are rare and may occur in immunocompetent patients or in association with immunosuppression related to HIV infection or organ or marrow transplantation. With the introduction of HAART, the incidence of PCNSL has decreased in HIV-infected persons. Of note, most cases of PCNSL are DLBCLs, but rare cases of PTCL, low-grade lymphoma, and Burkitt lymphoma have also been reported (Batchelor and Loefer, 2006). PCNSL may be multifocal in 20% to 49% of cases, with or without meningeal involvement (5%). A contrast-enhanced MRI should be performed, along with lumbar puncture with cerebrospinal uid analysis. A slit-lamp examination is important in the staging evaluation to rule out concurrent ocular involvement, which can occur in up to 20% of patients
at the time of diagnosis. Patients typically present with neurologic symptoms, and systemic symptoms are uncommon. A prognostic scoring system has been developed in PCNSL given the limitations of the Ann Arbor staging system and the IPI in this disease. The following factors are associated with a poor prognosis: age 60; performance status 1; elevated LDH; high cerebrospinal uid protein concentration; and tumor location within the deep regions of the brain. Patients with 0, 1 to 4, or 5 of these factors had 2-year OS rates of 80%, 48%, or 15%, respectively (Ferreri et al, 2003). Surgery in PCNSL is typically used to obtain a diagnostic biopsy, and full surgical resection confers no survival benet over biopsy alone. The median survival after surgery alone is approximately 1 to 4 months. Whole-brain radiation is associated with a high response rate of 90%, but the median survival is only 12 months. Although there have been no randomized controlled studies to establish the best therapy, in retrospective analyses, outcomes are superior when highdose methotrexate (2-8 g/m2) is incorporated into rst-line regimens. With this approach, the median survival is approximately 55 to 60 months, and 5-year survival is approximately 30%, suggesting that cure is possible in a proportion of patients. Rituximab has poor penetration across the blood brain barrier but is currently being tested in clinical trials given synergy with chemotherapy. In younger patients, the combination of whole-brain radiation and methotrexate is often used, but it has not been directly compared with methotrexate alone. Furthermore, in patients 60, the risk of neurotoxicity is high and manifests as dementia, ataxia, and incontinence, with a median time to onset of approximately 1 year. HDT and ASCT have been used in the salvage setting with a median survival from the time of relapse of 24 months. Temozolomide either alone or in combination with rituximab has shown an ORR of 26% and 53%, respectively, in relapsed and refractory patients. NHLs in children NHLs comprise 8% of cancers in children. There are striking variations of incidence by sex (male-to-female ratio of 2-3:1) and race (white-to-black ratio of 2:1, rare in Asian populations). There is an increased incidence in patients with congenital (ataxia-telangiectasia, Wiskott-Aldrich syndrome, and others) or acquired (posttransplantation) immunodeciency states. Prior EBV infection has been implicated in the pathogenesis of endemic (African) Burkitt lymphoma but is less common in sporadic American and European cases. The histologic subtypes of childhood NHL are signicantly different from those in adults. Burkitt lymphomas (mature B-cell) account for one third of cases, lymphoblastic lymphomas (primarily T cell) account for 30%, and largecell lymphomas of multiple lineages account for 25% to 30%.
Hodgkin lymphoma | 541
Follicular lymphomas are rare in children. However, chromosomal translocations and molecular features are similar to those in adults with the same lymphoma subtype. Childhood NHLs are staged using the Murphy staging system. Therapy depends on the stage. Ninety percent of patients with stage I or II Burkitt or large-cell lymphoma can be cured with 9 weeks of CHOP-like chemotherapy. Using the same regimen, only 70% of patients with stage I or II lymphoblastic lymphoma are cured; adding a 1- to 2-year continuation phase of treatment with methotrexate, mercaptopurine, vincristine, and prednisone may decrease the relapse rate, although this has not been denitively established. CNS prophylaxis may be limited to patients with lower stage NHL who have head and neck primary sites. Stage III and IV (initial involvement of the CNS and/or bone marrow) lymphomas require more intensive chemotherapy. Burkitt and large B-cell lymphomas can be cured in 80% to 85% of cases with 3 to 8 months of chemotherapy that includes cyclophosphamide, doxorubicin, dexamethasone, vincristine, high-dose methotrexate, and high-dose cytarabine. A similar protocol that also includes ifosfamide and etoposide has cured almost 80% of children with advanced-stage ALCLs. Lymphoblastic lymphomas are cured in a similar fraction of cases with 2 to 3 years of treatment with protocols similar to those for higher risk acute lymphocytic leukemia in children (see Chapter 17). CNS chemoprophylaxis with intrathecal medications is an important component of treatment of all subtypes in children with advanced-stage NHLs. Some protocols still use low-dose (12-18 Gy) cranial irradiation as part of CNS prophylaxis for patients with advanced lymphoblastic lymphomas.
Hodgkin lymphoma
HL is a relatively uncommon malignant lymphoma, with an average incidence of approximately 8000 cases per year in the United States; HL accounts for approximately 30% of all lymphomas. HL is most commonly diagnosed in younger patients, with an average age at diagnosis of 30 years. Patients with HL often present with an asymptomatic mass, typically in the cervical region, but constitutional symptoms including fever, night sweats, and weight loss can also occur. With high cure rates, a reduction in the long-term treatment-related morbidity and mortality is now a major goal of newer therapeutic approaches. Pathology The classic histologic nding associated with HL is the Hodgkin Reed-Sternberg (HRS) cell, a large cell that may be bi- or multinucleate and that contains large acidophilic nucleoli. The origin of these cells has long been debated but now has been demonstrated to be of B-cell origin in most cases. The use of micromanipulation and PCR analysis of single cells reveals that these cells usually comprise a monoclonal population of B cells, likely derived from germinal centers. Because the origin of the HRS cell is now rmly established to be a lymphoid cell, the term Hodgkin lymphoma is preferred over Hodgkin disease. It is now known that HL is composed of 2 disease types due to differences in pathology and also clinical behavior (Table 18-3): CHL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). CHL has 4 subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted, which all differ in their sites of presentation, clinical features, and histologic appearance. Classical Hodgkin lymphoma CHL accounts for 95% of all HLs, with the majority of patients presenting at age 15 to 35 years. A recent population-based study has demonstrated an increased risk of HL in patients with a diagnosis of infectious mononucleosis in the previous 2 years, suggesting an association of the disease with recent primary EBV infection. EBV is postulated to play a role in the development of CHL, but it is only found in a proportion of cases, predominantly in the mixed cellularity and lymphocyte-depleted subtypes. EBV-positive CHL is also more commonly encountered in the setting of HIV infection, and the incidence has not declined in the era of HAART. EBV-infected HRS cells express the EBV protein LMP-1, which is postulated to have transforming and antiapoptotic properties. CHL is characterized by a variable number of HRS cells admixed with a rich inammatory
Key points
DLBCL is the most common subtype of aggressive NHL in Western populations; T- and NK-cell subtypes are more common in Asian populations. The IPI score and the cell of origin phenotype provide useful prognostic information in DLBCL. R-CHOP chemotherapy results in cure in 50% of patients with DLBCL. The IPI and cell of origin phenotype remain prognostic in the rituximab treatment era. Relapsed aggressive lymphoma patients who have chemotherapy-sensitive disease to a second-line regimen (at least a PR) should be referred for HDT with ASCT. PTCLs have an inferior outcome to DLBCL. The exception is ALK-positive ALCL, which has a high cure rate with CHOP chemotherapy. Most children with NHL have aggressive subtypes; however, high cure rates are seen with multidrug chemotherapy regimens. Patients with congenital or acquired immunodeciency have an increased risk of lymphoma and often respond poorly to therapy.
542 | Lymphomas
background, the composite of which varies according to the CHL subtype. The classic HRS cells are large with at least 2 nuclear lobes of nuclei giving the appearance of owls eyes. The HRS cells represent a minority of the cellular inltrate ranging in frequency from 1% to 10%. The classic phenotype of the HRS cell is CD15, CD30, and CD45. Nodular sclerosis CHL Nodular sclerosis CHL accounts for 70% of CHL in Western populations. There is an equal prevalence in males and females, and the average age of presentation is 15 to 35 years. Typically patients present with mediastinal adenopathy, often with bulky disease, and B-symptoms are common (40%). The second most common site of involvement is the cervical region. Splenic and/or lung involvement is seen in approximately 10%, and bone marrow involvement is rare (3%). Morphologically, a nodular growth pattern is seen, with nodules separated by characteristic brotic bands. LMP-1 EBV protein is found in approximately 10% to 40% of cases. Mixed cellularity CHL Mixed cellularity CHL accounts for 20% to 25% of CHL and is more frequently encountered in patients with HIV infection and in developing countries. The median age of presentation is 38 years, and 70% of patients are male. B-symptoms are more common than in nodular sclerosis CHL. Peripheral adenopathy is common, but mediastinal involvement is rare. Bone marrow disease is found in 10% of patients, and splenic involvement occurs in 30%. Scattered HRS cells are seen in a diffuse or occasionally vaguely nodular mixed inammatory background without the bands of brosis encountered in nodular sclerosis CHL. The prognosis of patients with mixed cellularity CHL was less favorable compared with nodular sclerosis CHL when radiotherapy was used as a single modality. However, with combination chemotherapy, outcomes approximate those seen in nodular sclerosis CHL. Lymphocyte-rich CHL Lymphocyte-rich CHL comprises 5% of all CHLs, and patients most frequently present with peripheral adenopathy and stage I or II disease. Mediastinal involvement and B-symptoms are rare. Morphologically, lymphocyte-rich CHL can be difcult to distinguish from NLPHL most commonly occurring with a nodular growth pattern (see later section on NLPHL), but they can be distinguished by immunophenotyping. The atypical cells of lymphocyte-rich CHL have the same immunophenotype as the HRS cells of other subtypes of CHL. The prognosis is excellent in part because of predominantly early-stage disease.
Lymphocyte-depleted CHL Lymphocyte-depleted CHL is a rare subtype of CHL comprising 1% of cases in Western populations. Most patients are male, the median age of onset is 30 to 37 years, and like mixed cellularity CHL, it is more commonly encountered in HIV patients and in developing countries. There is a predilection for intra-abdominal lymphadenopathy and extranodal involvement, including the bone marrow. Lymphocytedepleted CHL is more likely to occur as advanced-stage disease with B-symptoms. The morphology is variable; however, there is a predominance of HRS cells compared with the background lymphocytes. Coexpression of CD30 and Pax5 can be helpful in differentiating lymphocyte-depleted CHL from ALK-ALCL. With combination chemotherapy, the prognosis is similar to other stage-matched CHL subtypes.
Nodular lymphocyte-predominant HL NLPHL is differentiated from CHL based on distinct pathologic and clinical features. The neoplastic cells in NLPHL are known as lymphocyte-predominant cells or the so-called popcorn cells based on their characteristic appearance. They differ immunophenotypically by expression of B-cell markers such as CD20, CD79a, BCL6, and CD45 but lack CD15 and CD30. Morphologically, a nodular pattern is typically seen predominantly composed of nonneoplastic cells including small lymphocytes intermixed with lymphocytepredominant cells. At the molecular level, clonally rearranged immunoglobulin genes are found. Differentiating NLPHL from T-cellrich B-cell lymphoma (TCRBCL) can be challenging; however, the presence of small B cells and CD4/ CD57 T cells favors NLPHL, whereas the absence of small B cells and the presence of CD8 cells and TIA1 cells favors primary TCRBCL. As outlined earlier, immunophenotyping can differentiate NLPHL from the morphologically similar lymphocyte-rich CHL. Clinically, patients are typically male, ranging in age from 30 to 50 years and presenting with localized peripheral adenopathy with stage I or II disease. Mediastinal and splenic involvement is rare. Late relapses are more common in NLPHL compared with CHL. There is also an increased risk of secondary NHL, most commonly DLBCL, including TCRBCL, compared with patients with CHL. A recent study evaluated the frequency of transformation to aggressive lymphoma in a cohort of patients with NLPHL with mature follow-up and found that the 10-, 15-, 20-, and 25-year risks were 7%, 15%, 31%, and 36%, respectively, with no apparent plateau (Al-Mansour et al, 2010). Because this development can occur decades after the primary diagnosis, patients need to have ongoing surveillance, and biopsy is imperative at the time of disease recurrence. It has been speculated that given the B-cell
Table 18-10 Prognostic factors for advanced-stage Hodgkin lymphoma. Male sex Stage IV disease Age 45 Serum albumin 4 g/dL Hemoglobin 10.5 g/dL White blood cell count 15,000/L Lymphocyte count 600/L or 8% of total white blood cell count From Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin disease. N Engl J Med. 1998;339:15061514.
Table 18-11 Rates of freedom from progression and overall survival at 5 years according to grouped prognostic scores. Prognostic score 03 4 5-year freedom from progression (%) 70 47 5-year overall survival (%) 83 59
Frequency (%) 81 19
From Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin disease. N Engl J Med. 1998;339:15061514.
0 to 3 results in a 5-year freedom from progression of 70% compared with 47% for a score of 4 (Table 18-11).
phenotype and observation of late relapses that NLPHL maybe more related to indolent B-cell lymphoma. However, recent gene expression proling studies demonstrated a high degree of similarity to CHL as well as the tumor cells of TCRBCL; in contrast, the signature had a low degree of relatedness to follicular lymphoma (Brune et al, 2008). Staging and prognostic factors The Ann Arbor staging system for HL has been used for 25 years (Table 18-5). The same staging procedures as described earlier for NHL are also performed in HL, including CT scans of the neck, chest, abdomen, and pelvis; bone scans are indicated in the presence of bone pain or other localizing symptom. Bone marrow aspiration and biopsy are indicated in the presence of advanced-stage disease, B-symptoms, or cytopenias, but they have a small yield of positive ndings in asymptomatic clinically early-stage patients. PET scanning has excellent sensitivity, and several studies have demonstrated improved sensitivity and specicity over CT alone for detecting residual disease. In the recently revised response criteria, PET is recommended before treatment but not required due to current limitations of cost and availability. PET is recommended after treatment and may be particularly helpful if there is a residual mass on CT imaging (Table 18-8). As indicated earlier, in the revised response criteria, a CR is assigned if the PET scan is negative even if a residual mass is present on CT imaging. Staging laparotomy and splenectomy and bipedal lymphangiograms are no longer required in HL management. A prognostic scoring system has been developed for advanced-stage HL after analyzing outcome data for 5000 patients who were primarily treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/ ABVD. Regression analysis identied 7 factors, consisting of 3 clinical risk factors and 4 laboratory risk factors, that were predictive of outcome; these factors are shown in Table 18-10 (Hasenclever and Diehl, 1998). Each factor has approximately equal weight in reducing the freedom from progressive disease, so a simple additive score is possible. A score of
Key points
HL is most common in adolescents and young adults. There are 2 subtypes of HL: CHL and NLPHL. Most HLs are derived from B cells; nodular sclerosis is the most common subtype in Western populations. Accurate staging is the most important factor in determining the therapeutic approach.
Treatment of HL In North America, patients are typically divided into those with limited- or early-stage disease (stage I or II disease, nonbulky [10 cm], and no B-symptoms) and advancedstage disease (stage III or IV disease, bulky stage II, or B-symptoms) for treatment stratication (Table 18-12). Of note, stage I patients rarely present with B-symptoms, but if they do, they are typically treated with limited-stage protocols. In Europe, other staging categories have also been developed. European HL study groups have further stratied early-stage patients into those with favorable versus unfavorable risk factors (large mediastinal mass, elevated erythrocyte sedimentation rate, 34 involved nodal groups, age 50 years, and extranodal disease). Treatment of early-stage HL The prognosis of patients with early-stage HL is excellent, with a 5-year OS rate of 95% (Meyer et al, 2005). Thus, the current challenge is to maintain high cure rates and minimize long-term toxicities of therapy, particularly given the young
Table 18-12 Staging of patients with Hodgkin lymphoma in North America for treatment stratication. Early (limited) stage Stage I or II, no bulky disease, no B-symptoms Advanced stage Stage III or IV, bulky stage II, or B-symptoms
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age of presentation of most patients. Options for these patients include radiation therapy alone, a combination of chemotherapy and radiation therapy, or chemotherapy alone. Irradiation has been historically used in the treatment of early-stage HL largely because it predated chemotherapy. Radiation therapy alone was used for early-stage disease for patients staged by laparotomy and conrmed to have pathologic stage IA or IIA disease. With a negative laparotomy, extended-eld radiation (eg, mantle with or without periaortic elds) induces CRs in 95%. Long-term disease-free survival is achieved in approximately 80% of patients, and because they generally remain chemotherapy sensitive at relapse, 90% are alive 10 years from diagnosis. However, approximately 20% of patients are upstaged at the time of laparotomy and require an extended course of chemotherapy. Because laparotomy is no longer used, there are signicant advantages to incorporating chemotherapy into the treatment of early-stage HL. A current approach for earlystage patients is the combination of brief chemotherapy with radiation therapy. The inclusion of chemotherapy plus irradiation eliminates the need for surgical staging with laparotomy because the systemic therapy will eliminate microscopic disease, and reducing the number of cycles may decrease the short- and long-term toxicities of the chemotherapy. From studies in advanced-stage HL (see next section on treatment of advanced-stage HL), ABVD emerged as the obvious choice for patients with early-stage HL, balancing high efcacy with low toxicity. Several studies have demonstrated that brief chemotherapy with ABVD (24 cycles) followed by irradiation is very effective for treating early-stage HL. However, there is also great interest in reducing the dose and eld of radiation to minimize long-term toxicities such as secondary malignancies and cardiac disease (Aleman, van den BeltDusebout, et al, 2003), while maintaining high cure rates. Mature follow-up from a small randomized controlled study from the Milan group that compared ABVD plus subtotal nodal radiotherapy with ABVD plus IFRT demonstrated 12-year freedom from progression and OS rates of 94%, with no difference in outcome between the radiation groups (Bonadonna et al, 2004). More recently, studies of involved nodal radiation, which reduces radiation eld size even further, support that margins can be limited to 5 cm without compromising relapse rates (Campbell et al, 2008). The German Hodgkin Study Group has recently evaluated the optimal number of cycles of ABVD with IFRT in patients with early-stage HL. More than 1000 patients were randomized to receive either 2 or 4 cycles of ABVD followed by a second randomization of 30 or 20 Gy of IFRT. At a median follow-up of just over 2 years, there was no difference in the freedom from treatment failure or OS between any of the treatment groups (Engert et al, 2005); however, follow-up remains short.
Recognizing that there are long-term complications of RT, chemotherapy alone has been explored in the treatment of early-stage HL. Many of the early trials, however, lack relevance today because they relied on staging laparotomy, included patients who would be considered advanced stage, and used chemotherapy less effective than ABVD. A recently published randomized study in early-stage HL conducted by the National Cancer Institute of Canada and the ECOG compared ABVD alone versus either extended-eld radiation for patients with favorable risk factors or ABVD for 2 cycles followed by extended-eld radiation in patients with unfavorable risk factors (age 40 years, erythrocyte sedimentation rate 50 mm/h, mixed cellularity and lymphocytedepleted histology, and 4 disease sites). There was a modest but statistically signicant difference in PFS favoring the radiation-containing therapy (93% in ABVD alone vs 87% in RT-containing therapies; P .006); however, OS was similar (96% in ABVD alone vs 94% in RT-containing therapies; P .06), suggesting that the advantage in PFS is offset due to deaths related to other causes. Interestingly, in a subgroup analysis, for patients who achieved a CR by CT imaging after 2 cycles of ABVD, a similar PFS was observed comparing the chemotherapy alone and RT-containing arms. Most centers still consider brief chemotherapy with ABVD and IFRT to be the standard approach in patients with early-stage disease, and trials are planned to study chemotherapy alone integrating a PET-adapted approach in the hope of avoiding radiotherapy in patients who are otherwise cured with chemotherapy alone. Several studies in children have investigated the use of chemotherapy alone for early-stage HL. Results in limited numbers of patients suggest that CR and EFS rates are similar to those seen with irradiation alone. Further studies with larger numbers of patients are necessary to evaluate the relative efcacy and toxicities of these approaches (see discussion later in this section). Treatment of advanced-stage HL Patients with B-symptoms, bulky disease, or stage III or IV disease require an extended course of chemotherapy. Multiagent chemotherapy with MOPP was rst developed in the 1960s and achieved high response rates and long-term survival in approximately 50% to 60% of patients (Table 18-13). ABVD was developed by the Milan group in 1973 and has partial noncross-resistance with MOPP and can cure approximately 20% of patients who are not cured with MOPP. Hybrid and alternating regimens were tested in the 1980s and were shown to be superior to MOPP alone. However, in a large randomized Cancer and Leukemia Group B trial comparing ABVD versus MOPP/ABVD versus MOPP, both ABVD-containing regimens had a superior 5-year
Table 18-13 Chemotherapy regimens for Hodgkin lymphoma. ABVD Doxorubicin Bleomycin Vinblastine Dacarbazine MOPP Mechlorethamine Vincristine Procarbazine Prednisone MOPP/ABVD MOPP and ABVD alternated every 28 days MOPP/ABV hybrid MOPP and ABV alternating within each treatment cycle Stanford V (12-week regimen) Meclorethamine Doxorubicin Vinblastine Vincristine Bleomycin Etoposide Prednisone Plus irradiation 36 Gy to initial sites of disease 5 cm BEACOPP Bleomycin Etoposide Doxorubicin Cyclophosphamide Vincristine Procarbazine Prednisone Plus irradiation to initial sites of disease
failure-free survival (P .04); however, ABVD alone emerged as being the optimal choice because it had equivalent efcacy to the alternating regimen but did not cause sterility or premature menopause and was less leukemogenic. For this reason, ABVD is the current standard regimen for advanced HL in adults. Of note, there was no statistically signicant difference in OS across the arms, which reects the high salvage rate with secondary treatment. Treatment is generally given for 6 to 8 cycles. There is no role for additional radiotherapy in patients with stage III or IV disease who achieve a CR using conventional imaging. A recent study by Aleman, Raemaekers, et al (2003) evaluated the role of IFRT for patients with advanced disease in CR after chemotherapy with MOPP/doxorubicin, bleomycin, vinblastine (ABV). No improvement was seen for those receiving radiation versus observation after chemotherapy, and there was a trend toward decreased 5-year survival in the group that received radiation. Patients in PR all received IFRT and had an
outcome that was similar to those who achieved a CR. However, given the high frequency of residual disease in this population, a substantial proportion of these patients may have actually been in a CR and would not have required the additional radiotherapy. With the availability of PET scanning, studies are ongoing evaluating whether radiotherapy can be withheld in patients in PR by CT imaging but in CR by PET criteria (ie, PET negative). Patients with a bulky mediastinal mass (10 cm or more than one third of the maximum diameter of the chest) may benet from adjuvant radiation therapy to the residual mass after chemotherapy because of a higher rate of local relapse. Whether PET scanning will be useful in identifying patients with active residual disease versus brosis, and thus the need for local irradiation, remains to be determined. Two newer regimens have also been used in advancedstage HL. The Stanford V regimen (ie, mechlorethamine, doxorubicin hydrochloride, vinblastine, vincristine, bleomycin, etoposide, and prednisone) involves weekly chemotherapy for 12 weeks, with myelosuppressive agents alternating with nonmyelosuppressive agents. Patients also receive 36 Gy of irradiation to sites of original tumor bulk (dened as 5 cm) following completion of chemotherapy. The initial single-arm study of 142 patients reported by Horning et al (2002) included 96 patients with stage III or IV disease and 46 patients with stage I or II disease plus a mediastinal mass greater than one third of the maximum chest diameter. The disease-free survival was 89% with a median follow-up of 5.4 years. One quarter of the patients required hospitalization during therapy due to acute toxicities, usually related to myelosuppression; there were no treatment-related deaths. Late toxicity at 5 to 6 years appeared minimal, although longer follow-up will be required to assess any late effects or second malignancies related to the combined chemotherapy plus irradiation. The results of an ongoing intergroup study comparing the Stanford V regimen with ABVD are awaited to determine its role in rst-line therapy. The German Hodgkin Study Group studied a dose-escalated and accelerated regimenbleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP)in 1200 patients with advanced HL (Table 18-13). When compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD, BEACOPP and an increased-dose version of BEACOPP (escalated) had improved freedom from treatment failure at 5 years, and escalated BEACOPP had a superior 5-year OS compared with COPP/ABVD (P .002). Of note, a large proportion of patients in this study received radiotherapy to sites of bulky disease (5 cm) or residual tumor. This analysis was updated at the ASH meeting in 2007 with a median follow-up of 112 months. At 10 years, the freedom from treatment failure rates were 64%, 70%, and 82% and OS
546 | Lymphomas
rates were 75%, 80%, and 86% for COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP escalated (arm C), respectively (P .0001). Benets were seen across the prognostic subgroups; however, they were most profound in the group with 4 factors. Escalated BEACOPP was superior to standard BEACOPP, but there was also a higher rate of secondary AML after escalated BEACOPP. Furthermore, there is a high rate of infertility in men and women (Sieniawski et al, 2008; Behringer et al, 2005). Because of the toxicity of therapy with BEACOPP, there is interest in targeting the patient population who would benet the most (ie, those with high-risk disease). A trial is currently ongoing comparing ABVD with BEACOPP in patients with 3 Hasenclever prognostic risk factors. Recent interest has also turned to the use of PET scan to guide the use of more dose-intensive therapy. The prognostic value of a PET scan after 2 cycles of ABVD in patients with advanced-stage HL (stages IIB-IVB) was recently reported whereby therapy was not changed based on the results of the PET. The 2-year PFS for patients with a PET-positive scan after 2 cycles of ABVD was 12.8% compared with 95% for patients with a PET-negative result (P .0001) (Gallamini et al, 2007). The results of the interim PET overshadowed the prognostic value of the IPS, and even patients with a score of 3 to 7 who achieved a PET-negative status had an excellent outcome. Studies are under way in the United Kingdom and the United States evaluating the role of escalation of therapy from ABVD to BEACOPP in patients who have a PET-positive result after 2 cycles of ABVD. Studies have also evaluated the benet of HDT with ASCT in rst remission for patients with high-risk disease. A recent European intergroup trial randomized 163 patients with unfavorable advanced disease with a CR or PR to 4 cycles of standard induction therapy to receive 4 more cycles of standard therapy versus HDT with autologous stem cell rescue. Although there was a slightly lower risk of relapse in the high-dose arm, there was no difference in OS, indicating that standard-dose chemotherapy is appropriate for highrisk patients. Treatment of relapsed/refractory disease The approach to patients with relapsed HL depends on the primary therapy and duration of initial remission. Those treated with irradiation alone for early-stage disease are generally chemotherapy sensitive at relapse, and 50% to 80% achieve long-term disease-free survival with standard chemotherapy. However, the majority of patients who relapse will have received chemotherapy as a component of their primary therapy. Patients who relapse late (12 months) after a CR may be treated with combination chemotherapy; 50% to 60% remain disease free at 5 years. Patients who
relapse within 12 months are much less likely to achieve remission and long-term disease-free survival with chemotherapy alone. Other poor prognostic signs in patients at relapse include advanced stage, relapse in extranodal sites, relapse in previously irradiated sites, and the presence of B-symptoms. Patients who have high-risk factors or relapse 12 months after completion of primary chemotherapy should be considered for HDT and ASCT. Patients who relapse 12 months after completion of chemotherapy or in previously unirradiated sites can potentially be treated with chemotherapy with or without radiotherapy; however, given the excellent results with HDT and ASCT, some groups also consider this approach in this subgroup of patients. Hematopoietic stem cell transplantation For patients whose disease is refractory to primary therapy or relapses shortly after an initial response, standard-dose chemotherapy is unlikely to be benecial. High-dose chemotherapy with autologous stem cell support has been demonstrated to provide long-term disease-free survival to some patients in this circumstance. Additional irradiation to areas of bulky disease may also be helpful. The 5-year PFS is approximately 30% in patients with refractory HL who undergo HDT and ASCT. The most commonly used HDT regimens are carmustine, etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, carmustine, and etoposide (CBV). Prior to transplantation, a salvage regimen is often given if the patient is symptomatic or to arrange for the logistics of the transplantation. Unlike in aggressive lymphoma, the purpose of this chemotherapy is not to test chemosensitivity because even disease that does not respond to standard-dose chemotherapy can be cured with HDT/ASCT. HL in children HL represents 5% of childhood cancers. The disease is uncommon before age 10. Males are affected more frequently than females, especially in patients younger than 10 years. The incidence of EBV-associated disease varies widely by age, histologic subtype, and racial group (Asian 93%, white 46%, African American 17%). The incidence of histologic subtypes also differs from adults, with lymphocyte predominant in 1% to 15%, mixed cellularity in 30%, and nodular sclerosis in 40% to 70%. Lymphocyte-depleted HL is rare, except in HIV-infected patients. Treatment of HL in children must take into account 2 important differences from adults: ongoing growth and development and a longer expected life span after cure. Thus, there is increasing concern regarding late complications for treatment in children, including second cancers (AML,
Acknowledgment | 547
breast cancer, and NHL), cardiomyopathy, sterility, and others. To address this problem, several studies have investigated the use of chemotherapy alone for treatment. In one trial for lower stage (IA, IIA, or IIIA) HL, disease-free survival was 87% for 83 patients treated with chemotherapy (MOPP 3, ABVD 3) alone and 91% for 85 patients treated with chemotherapy plus irradiation (25.5 Gy IFRT). In a similar trial for patients with higher stage (IIB, IIIA2, IIIB, or IV) disease, EFS was 79% for 81 patients treated with MOPP 4 plus ABVD 4 alone and 80% for 80 patients treated with chemotherapy plus irradiation (21 Gy). OS in the latter study was 96% after chemotherapy alone and 87% after combinedmodality treatment. In a third trial, 501 patients (all stages) who achieved a CR after 2 or 3 courses of COPP/ABV were randomized to receive irradiation (21 Gy IFRT) or no further therapy. EFS at 3 years favored the irradiated cohort (93% vs 85%), but OS was 98% in both groups. Thus, chemotherapy alone may cure 80% to 90% of children with HL. Patients who relapse will often respond to subsequent treatments including chemotherapy, irradiation, and stem cell transplantation. Current studies are directed at development of less toxic chemotherapy regimens and prediction of chemotherapy failure by assessment of the rapidity of response to initial chemotherapy. Long-term complications of HL therapy An important issue in the current management of patients with HL concerns the long-term morbidity of the various approaches. As increased numbers of patients were cured of their diseases in the 1970s and 1980s, long-term follow-up has demonstrated a high rate of late toxicity. In large cohorts of patients followed at Stanford from 1960 to 1995 and at the Dana-Farber Cancer Institute and Massachusetts General Hospital from 1969 to 1997, the risk of death from other causes surpasses that from HL at approximately 15 years. The causes of these late deaths are predominantly second malignancies and cardiovascular events, many of which can be attributed to radiation or chemotherapy. Thus, long-term follow-up of HL patients is an important component of management, as is appropriate patient education regarding health maintenance and comorbid risk factors such as tobacco use. Second solid tumors are attributed to prior radiation, the majority of which occur within or on the border of the prior radiation eld. The malignancies commonly identied are breast, lung, GI, or thyroid carcinomas and sarcomas of soft tissue and bone. There is typically a latent period of at least 5 to 10 years, and the risk of secondary cancers continues for 30 years from initial treatment. The best-studied secondary tumor is breast cancer, which has its highest incidence in adolescent girls treated with radiation as well as women treated before 30
years of age. Breast cancers begin to appear at the end of the rst decade following treatment and continue to increase with time, with an estimated incidence of 30% by 40 years of age in these patients. For this reason, mammographic and selfexamination surveillance is recommended to start within 10 years of irradiation and to continue indenitely. Cardiovascular complications also occur following radiation therapy. These include myocardial infarction from damage to the coronary arteries, pericardial disease, and diffuse myocardial disease. Males and older patients are at highest risk, but all patients are at risk for vascular damage within their radiation ports. Another common adverse effect of radiation therapy is hypothyroidism, which occurs in approximately 50% of patients treated with radiation to the thyroid bed. The long-term toxicities of chemotherapy depend on the regimen. MOPP is associated with sterility, an increased risk of MDS, and secondary AML. ABVD has not been associated with sterility or MDS/leukemia but does have the risks of pulmonary and cardiac toxicity from bleomycin and doxorubicin, respectively. The risks of high-dose chemotherapy and combined chemotherapy and radiation therapy have become more of a concern as more patients receive this therapy. An increased incidence of MDS/AML has been documented within 5 to 7 years of HDT, which is in addition to the acute toxicity of transplantation. This likely reects the cumulative marrow toxicity of alkylating agents, etoposide, and radiation therapy. Patients with a history of HL also have an increased incidence of NHL, but the contributions of radiation, chemotherapy, or the immune suppression of HL itself are unclear.
Key points
ABVD is the standard therapy for advanced-stage HL. Limited-stage HL shows high rates of durable remission following 2 to 4 cycles of chemotherapy and IFRT or extendedeld radiation therapy. Patients with primary refractory disease or those relapsing after initial chemotherapy-induced remission should be evaluated for HDT and autologous stem cell rescue. Late radiation-induced complications include solid tumors within the radiation eld and cardiovascular disease; the risk persists 20 years after treatment. Late chemotherapy-induced complications include cardiac dysfunction, lung disease, development of MDS or AML, and sterility.
Acknowledgment
The authors thank Dr. Bruce M. Camitta for providing the discussion regarding NHL and HL in children.
548 | Lymphomas
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Immunodeciency-associated lymphoproliferative disorders

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Hodgkin lymphoma
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Chapter 18 Lymphomas Kerry J. Savage and Stephanie A. Gregory

Go to original online chapter: http://ash-sap.hematologylibrary.org/cgi/content/full/2010/1/511

A publication of the American Society of Hematology

Overview of lymphocyte development

Overview of lymphocyte development | 513

CD25/, CD38/ CD11c, CD25, CD103

Burkitt lymphoma ALCL, ALK-positive

TdT CD2, CD3/, EMA

Overview of lymphocyte development | 515

Non-Hodgkin lymphomas | 517

Table 18-5 Ann Arbor staging system.*

Non-Hodgkin lymphomas | 519

Risk factors (no.) 0, 1 2 3 4, 5 0 1 2 3

Distribution of cases (%) CR rate (%) 5-year OS (%) 35 27 22 16 22 32 32 14 87 67 55 44 92 78 57 46 73 51 43 26 83 69 46 32

Table 18-8 Recommended timing of PET/CT scans in lymphoma clinical trials.

Non-Hodgkin lymphomas | 521

Non-Hodgkin lymphomas | 523

EPOCH Etoposide Vincristine Doxorubicin Cyclophosphamide Prednisone

Non-Hodgkin lymphomas | 525

Non-Hodgkin lymphomas | 527

Non-Hodgkin lymphomas | 529

Non-Hodgkin lymphomas | 531

Non-Hodgkin lymphomas | 533

Non-Hodgkin lymphomas | 535

Non-Hodgkin lymphomas | 537

Immunodeciency-associated lymphoproliferative disorders | 539

Immunodeciency-associated lymphoproliferative disorders

Hodgkin lymphoma | 541

Hodgkin lymphoma | 543

Hodgkin lymphoma | 545

Immunodeciency-associated lymphoproliferative disorders

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