Richard F. Little and Wyndham H. Wilson
INTRODUCTION
The non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoid tumors that have distinctive clinical and biologic behaviors. Currently tumor classification by the World Health Organization (WHO) establishes specific designations within the various lymphomas, whereas older classification systems did not do this. For example, in the older Revised European-American Lymphoma Classification or earlier systems such as the Kiel or the Lukes-Collins systems, tumors were not differentiated biologically. B- and T-cell tumors were not classified separately. Consequently, many findings from older clinical trials reflect outcomes based on the inclusion of divergent entities with markedly different clinical behaviors. Comparing newer trial data to older “historic control” trial data is generally not valid for this reason, among others. Current clinical trial design, inclusion criteria, and interpretation of findings must take these advances in classification into account.
This chapter focuses on the major disease entities of NHL while mentioning the spectrum of lymphoid diseases in order to emphasize the imprecision of the term non-Hodgkin lymphoma. This overview is intended to impress that accurate diagnosis of the specific NHL subtype is critical to interpretation of clinical trials data, to foster improved therapeutics in the future, and to understand individual patient management.
Refinement in diagnostic resolution is an evolving science. Recent advances have led to resolution of clinically relevant molecular-based distinctions among lymphomas. For example, gene transcription signatures enable distinction of multiple subtypes of diffuse large B-cell lymphoma (DLBCL). While some of these methods are not suited for everyday clinical practice, emerging algorithms to classify lymphomas based on immunohistochemistry may facilitate incorporation of important differences into clinical practice in the future.
EPIDEMIOLOGY
A steady increase in the age-adjusted incidence of lymphomas per 100,000 persons has been documented with 11.1 cases in 1976, 19.0 in 2000, and 22.7 by 2008. Approximately one-third of the increase may be attributed to a combination of iatrogenic immunosuppression and the AIDS epidemic. In more recent years, NHL cases attributable to HIV infection have decreased consequent to effective combination antiretroviral therapy (cART). Other potential causes include increased exposure to environmental carcinogens. Most, though not all, NHL types occur more commonly in males, and whites are affected more than blacks.
PATHOPHYSIOLOGY
A major risk factor for NHL is an abnormality of immune function (either immune deficiency or dysregulation). Examples include HIV infection, iatrogenic immune suppression, autoimmune diseases, and congenital immune deficiencies (e.g., Wiskott-Aldrich, X-linked lymphoproliferative disorder). Also, oncogenic viruses have been implicated. The gamma herpes viruses are linked to certain NHL subtypes, especially lymphomas associated with immune deficiency states. These include Epstein-Barr virus (EBV), which is highly associated with African Burkitt lymphoma (BL) and AIDS-related DLBCL; the Kaposi sarcoma-associated herpes virus (KSHV) (also known as human herpes virus-8 or HHV-8) is etiologically linked to primary effusion lymphomas (PELs) and multicentric Castleman disease, a rare lymphoproliferative disorder associated with increased risk of developing aggressive B-cell lymphoma. These latter two conditions are primarily seen in individuals with HIV infection. Other oncogenic viruses include the human retroviruses and RNA viruses. Human T-lymphotropic virus Type 1 (HTLV-1) is causative of adult T-cell leukemia/lymphoma (ATLL), and the hepatitis C virus (HCV) is associated with splenic marginal zone lymphoma. In addition to infectious agents, environmental and occupational exposures, especially organic compounds such as organophosphate insecticides have been linked to lymphoma risk.
CLASSIFICATION
The current WHO classification utilizes immunophenotypic, molecular, genetic, and clinical elements to distinguish NHL subtypes. New high-throughput technologies such as gene expression profiling (GEP), comparative genomic hybridization, single nucleotide polymorphism arrays, micro RNAs, methylation, acetylation, and tissue microarrays foster mechanistic understanding of lymphoma biology that may eventually inform targeted therapeutics. These technologies are not well suited to routine clinical application owing to expense and complicated performance characteristics of the tests. Efforts to develop simpler algorithms will be important for clinical application. Yet, currently available laboratory procedure should be applied in the clinical setting to classify lymphoid tumors appropriately. The text of this chapter presents the lymphoid tumors in the order of the 2008 WHO classification of lymphoid tumors (Table 16.1). Tables 16.2 to 16.5 provide summaries of molecular and immunophenotypic characteristics of selected tumors encountered in clinical practice.
NHLs are broadly classified as B-cell or T-cell lymphomas, depending on the lymphocyte lineage giving rise to the tumor. B-lymphocytes give rise to B-cell NHL, 88% of all NHL. T-lymphocytes give rise to T-cell NHL, 12% of NHL. Expression (or its lack thereof) of cell surface antigens and immunoglobulin proteins is dependent on the type of lymphocyte and its stage of differentiation. Analysis of these proteins in tumor cells is diagnostically useful as well as for determining tumor histogenesis. Importantly, no single immunophenotypic marker is specific for any tumor, and a constellation of features is required for specific diagnosis.
There is an increasing appreciation of the relationship between tumor tissue origin and clinical behavior. For example, those DLBCL with an activated B-cell-like gene signature (termed ABC-DLBCL) can be distinguished from those that have a germinal center-like signature (termed GCB-DLBCL), and the latter have a more favorable prognosis.
The WHO recognizes four major categories of lymphoid neoplasms: (1) B-cell neoplasms; (2) T and natural killer (NK) cell neoplasms; (3) Hodgkin lymphoma; and (4) immunodeficiency- associated lymphoproliferative disorders. The latter are considered distinct diagnostic entities, though they share similar characteristics with tumors arising in immunocompetent hosts. A cell of origin is postulated for each neoplasm, though this may not necessarily be the cell in which the initial transforming event occurs. Thus, the designated cell of origin represents the state of differentiation of the tumor cells that are seen in the tissues.
It can also be helpful to consider lymphoid neoplasms broadly in terms of the arm of the immune system from which the tumor arises: the innate or adaptive immune response. The innate immune responses are a first line of mucocutaneous defense not requiring antigen-presenting cells to initiate the immune response. Included in the innate immune systems are NK cells, CD3+ CD56+ T-cells or NK-like T-cells, and γδ T-cells. The innate immune system cells are mainly extranodal, and lymphomas arising from these cells thus tend to be extranodal. The adaptive immune response is more complex and specific for particular pathogens and capacity to develop memory. The complexity of the adaptive immune response not only gives rise to the molecular heterogeneity of many B-cell lymphomas, but also helps to determine the type of lymphoma as it relates to a particular B-cell stage of development. Most B-cell neoplasms tend to reflect the stages of normal B-cell differentiation and the lymph node architecture is highly relevant to this process: nodal neoplasms are more likely to be seen.
Table 16.1 2008 WHO Classification of Lymphoid Tumors
Precursor B- and T-Cell Neoplasms
Precursor B lymphoblastic leukemia/lymphoma
B lymphoblastic leukemia/lymphoma, NOS
B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
B lymphoblastic leukemia/lymphoma with T(9;22) (q34; q11.2; BCR-ABL1)
B lymphoblastic leukemia/lymphoma with t(v;11Q23); MLL rearranged
B lymphoblastic leukemia/lymphoma with t(12;21) (p13;22);TEL_AML1,(ETV 6-RUNX1)
B lymphoblastic leukemia/lymphoma with hyperdiploidy
B lymphoblastic leukemia/lymphoma with hypodiploidy (hypodiploid ALL)
B lymphoblastic leukemia/lymphoma with t(5;14) (q31;q32); IL-3-IGH
B lymphoblastic leukemia/lymphoma with t(1;19) (q23; p13.3);E2A-PBX1 (TCF3-PBX1)
Precursor T lymphoblastic leukemia/lymphoma
Mature B-Cell Neoplasms
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-prolymphocytic leukemia
Splenic marginal zone lymphoma
Hairy cell leukemia variant
Splenic B-cell lymphoma/leukemia, unclassifiable
Splenic diffuse red pulp small B-cell lymphoma
Hairy cell leukemia variant
Lymphoplasmacytic lymphoma/Waldeström macroglobulinemia
Heavy chain disease
γ Heavy chain disease
μ Heavy chain disease
α Heavy chain disease
Plasma cell myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone lymphoma (MALT lymphoma)
Nodal marginal zone lymphoma
Pediatric nodal marginal zone lymphoma
Follicular lymphoma
Pediatric follicular lymphoma
Mantle cell lymphoma
DLBCL, NOS
T-cell/histiocyte-rich large B-cell lymphoma
Primary DLBCL of CNS
Primary cutaneous DLBCL, leg type
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
Mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma A
LK-positive large B-cell lymphoma
Plasmablastic lymphoma
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
Primary effusion lymphoma
Burkitt lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between diffuse and large B-cell lymphoma and Burkitt lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between diffuse and large B-cell lymphoma and classical Hodgkin lymphoma
Mature T-Cell and NK-Cell Neoplasms
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Chronic lymphoproliferative disorder of NK cells
Aggressive NK-cell leukemia
Systemic EBV T-cell lymphoproliferative disease of childhood
Hydroa vacciniforme-like lymphoma
Adult T-cell leukemia/lymphoma
Extranodal NK/T-cell lymphoma nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sézary syndrome
Primary cutaneous CD30+ T-cell lymphoproliferative disorders
Primary cutaneous anaplastic T-cell lymphoma (ALCL)
Lymphomatoid papulosis
Primary cutaneous γδ T-cell lymphoma
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
Primary cutaneous CD4 positive aggressive small to medium-size T-cell lymphoma
Peripheral T-cell lymphoma, NOS
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, ALK+
Anaplastic large cell lymphoma, ALK−
Hodgkin Lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma
Classical Hodgkin lymphoma
Nodular sclerosis classical Hodgkin lymphoma
Mixed cellularity classical Hodgkin lymphoma
Lymphocyte-rich classical Hodgkin lymphoma
Lymphocyte-depleted classical Hodgkin lymphoma
Immunodeficiency-Associated Lymphoproliferative Disorders
Lymphoproliferative diseases associated with primary immune disorders
Lymphomas associated with HIV infection
Post-transplant lymphoproliferative disorders (PTLD)
Early lesions
Plasmacytic hyperplasia
Infectious mononucleosis-like
PTLD Polymorphic
PTLD Monomorphic PTLD (B and T/NK cell types)
Classical Hodgkin lymphoma type PTLD
ALCL, anaplastic large lymphoma; ALL, acute lymphoblastic leukemia; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; HHV8, human herpes virus-8; MALT, mucosa-associated lymphoid tissue; NK, natural killer; PTLD, post-transplant lymphoproliferative disorders.
Following are the specific disease entities in order of presentation of the 2008 WHO Classification of lymphoid tumors.1
Precursor B- and T-Cell Neoplasms
Specific entities are B lymphoblastic leukemia/lymphoma that are (a) not otherwise specified, and (b) those with recurrently genetic abnormalities. Those with t(9;22)(q34;q11.2); BCR-ABL1 have improved prognosis in the era of imatinib and later-generation tyrosine kinase inhibitors. T lymphoblastic leukemia/ lymphoma is termed lymphoma when the disease is confined to nodal masses and does not involve the peripheral blood and marrow. T-ALL comprises 25% of adult ALL. See Chapter 20 for discussion and treatment.
Mature B-Cell Neoplasms
These tumors range broadly in clinical behavior. The very indolent tumors have low curative potential but median survivals measured in years to decades. The aggressive tumors have varying curative potential but without treatment can have a rapidly fatal clinical course.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
The term small lymphocytic lymphoma is used for non-leukemic cases with tissue morphology and immunophenotype of chronic lymphocytic leukemia (CLL). There must be adenopathy and no cytopenias due to bone marrow infiltration. See Chapter 20 for discussion and treatment.
B-Prolymphocytic Leukemia
B-Prolymphocytic leukemia (BPLL), formerly considered a variant of CLL, is now recognized as a distinct aggressive poor-prognosis tumor with a median survival of about 3 years. Purine analogues such as fludarabine, cladribine, and pentostatin are associated with approximately 50% response rates (RRs), including some complete responses. Allogeneic stem cell transplant may offer curative potential in selected patients.
Splenic Marginal Zone Lymphoma
Splenic marginal zone lymphoma comprises <2% lymphoid neoplasms, but may account for the majority of otherwise unclassifiable CLL that are CD5−. It appears to be associated with hepatitis C infection. Indolent cases may be observed without therapy. Splenectomy can be effective. Systemic alkylating or purine analog therapy with rituximab may be used.
Hairy Cell Leukemia
Hairy cell leukemia (HCL) is a rare indolent lymphoid leukemia. Treatments include cladribine and pentostatin. Rituximab is also useful. Immunotherapy directed against CD22 is of interest. Targeted therapy exploiting the recent finding of BRAF mutations in HCL may prove effective, though limited data currently exists.
Splenic B-Cell Lymphoma/Leukemia, Unclassifiable
These include splenic diffuse red pulp small B-cell lymphoma, and hairy cell leukemia variant (HCLv). Both are indolent and may respond to splenectomy. HCLv may respond to immunotherapy directed at CD20 and/or CD22.
Lymphoplasmacytic Lymphoma
This tumor is the most frequent cause of Waldenström macroglobulinemia and is associated with marrow and nodal involvement with paraproteinemia (usually IgM). It is chemotherapy sensitive, but novel agents such as bortezomib, lenalidomide, bendamustine, azacitidine, and vorinostat have reported activity. Combined with rituximab, these agents are of interest and may prove to be useful. Some experts suggest autologous stem cell transplantation (ASCT), but this may not be suitable for some patients. Recent identification of a point mutation in the MYD88 gene leading to NF-κB activation may provide rationale for more targeted therapy in this disease, including use of bortezomib.
Heavy Chain Diseases
Heavy chain diseases (HCD) are characterized as gamma, alpha, or mu heavy chains. The gamma form ranges from indolent to aggressive behavior; mu HCD is slowly progressive; alpha HCD involves an immunoproliferative small intestinal disease that may remit with antibiotic therapy in early stages. Transformation to DLBCL and a fatal outcome is frequent.
Plasma Cell Neoplasms
Monoclonal gammopathy of undetermined significance, multiple myeloma, and other forms are increasingly appreciated to represent distinct entities with clonal evolution over the natural history of the diseases. For more details, see Chapter 30.
Extranodal Marginal Zone Lymphoma of Mucosa-associated Lymphoid Tissue
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is an indolent extranodal tumor comprised of morphologically heterogeneous small B-cell and scattered immunoblasts and centroblast-like cells. It comprises up to 50% of primary gastric lymphoma and is associated with Helicobacter pylori. Antibiotic therapy eradication of H. pylori can induce gastric MALT lymphoma remission in cases demonstrated to be associated with this infection. Other localized sites and cases not associated with H. pylori can be treated with surgery or low-dose radiation.
Nodal Marginal Zone Lymphoma
Nodal marginal zone lymphoma (NMZL) is a primary nodal B-cell neoplasm morphologically similar to MALT lymphoma. It is essential to rule out MALT, Hashimoto thyroiditis, or Sjögren syndrome.
Follicular Lymphoma
Follicular lymphoma (FL) arises from germinal center B-cells and comprises about 20% of all lymphomas, primarily affecting adults in the 6th decade. Cells express BCL2 protein related to t(14;18) (q32;q21), the genetic hallmark of FL. Widespread disease at diagnosis and bone marrow involvement is common. FL is graded by determining the content of centroblasts per high-power field (1–5 in grade 1, 5–15 in grade 2, and >15 n grades 3A and 3B. 3B reflects sheets of centroblasts without detectable centrocytes seen in 3A). This grading system has been criticized for lack of clinical relevance and poor interobserver reproducibility. Localized disease can be treated with radiation therapy alone. Asymptomatic disseminated disease may be watched. Symptomatic disease or disease-causing psychological distress can be managed in a variety of ways (as discussed below).
Primary Cutaneous Follicle Center Lymphoma
Primary cutaneous follicle center lymphoma (CFCL) generally presents on the head or trunk. This is distinguished from primary cutaneous DLBCL, leg type in that it has a variable number of centrocytes/ centroblasts as in FL. Rituximab and other immunotherapeutics are commonly used; disease control is variable.
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) generally presents with stage III or IV disease and peripheral blood involvement is common. Cell cycle protein cyclin D1 overexpression is almost always present. MCL generally affects older adult males. Although it behaves somewhat aggressively, this lymphoma appears to be incurable, though perhaps there is a curative potential with allogeneic transplantation in selected patients.
Diffuse Large B-Cell Lymphoma
DLBCL is a constellation of heterogeneous disease entities each with distinct morphologic, biologic, and clinical characteristics. These differences are associated with molecular and immunophenotypic findings that help to segregate the various entities into various subgroups.
DLBCL, not otherwise specified comprises around 30% of adult NHL. It can arise de novo or consequent to progression of other lymphoid malignancies such as CLL/SLL, FL, marginal zone lymphoma, or nodular lymphocyte-predominant Hodgkin lymphoma. Morphologic variants include centroblastic, immunoblastic, and anaplastic subtypes. Molecular subgroups include germinal center B-cell-like (GCB) and activated B-cell-like (ABC). Adjusted for clinical features such as the international prognostic index (IPI—see below), the 5-year overall survival (OS) for the GCB-like subset is superior to that of the ABC-like subset, establishing these as distinct clinicobiologic entities. Most are CD20+, a therapeutic target exploited to benefit survival with the use of monoclonal antibodies, particularly rituximab.
Other Diffuse Large B-cell Lymphoma Subtypes
T cell/histiocyte–rich large B-cell lymphoma accounts for <10% of DLBCL; it is found mainly in middle-aged males. The large B-cells are surrounded by abundant T-cells and histiocytes.
Primary DLBCL of the central nervous system (CNS) comprises <1% of NHL and approximately 2% of brain tumors; these occur mainly in older persons (median age 60 years) or those with immunosuppression. The latter are frequently associated with EBV in the tumor cells. Neurologic and psychiatric presentation is not uncommon. High-dose methotrexate forms the basis of therapy. Whole-brain radiation may prolong progression-free survival (PFS), though randomized study results show no survival advantage in comparison to high-dose methotrexate-based therapy alone. Radiotherapy induced late-term neurotoxicity can lead to severe cognitive deficit.
Primary cutaneous DLBCL, leg type occurs mainly in women with median age in the 70s. Presentation is generally an ulcerative red or bluish tumor on the leg, though other sites can be involved. Five-year survival is approximately 50%. Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is often used; relapse is common. Radiotherapy, immunotherapy, stem cell transplant are reported as being used in these patients.
EBV-positive DLBCL of the elderly generally occurs at age >50 years unassociated with prior immunodeficiency and can have an aggressive course.
DLBCL associated with chronic inflammation, as the name implies, arises in the setting of long-standing chronic inflammation, such as pyothorax or in chronic osteomyelitis. The inflammation appears to be etiologically related.
Lymphomatoid granulomatosis is a proliferation of EBV-positive B-cells with reactive T-cells in the setting of a poorly defined T-cell immune-impaired state. Advanced disease can involve brain, kidneys, lung, liver, and skin. Early lower-grade disease may be cured with interferon therapy.
Primary mediastinal (thymic) large B-cell lymphoma (PMBL) arises in the mediastinum and is of putative thymic B-cell origin. PMBL has distinctive clinical, immunophenotypic, and genotypic characteristics. Presenting features include localized disease, and signs and symptoms related to a large anterior mediastinal mass. Dissemination to multiple organs can occur. CD19 and CD20 are present, while CD10 and CD5 are absent. GEP indicates PMBL is a molecular type of DLBCL distinct from ABC- and GCB-like tumors. Phase II data suggests favorable outcome with dose-adjusted EPOCH-R chemotherapy.
Intravascular large B-cell lymphoma (IVLBCL) is a rare extranodal lymphoma. Growth within the lumina of capillaries and other smaller vessels, generally widely disseminated to virtually any organ and bone marrow is characteristic. Lymph nodes are not usually involved. This is an aggressive tumor poorly responsive to chemotherapy. Rituximab may have activity.
ALK-positive large B-cell lymphoma is also known as ALK-positive plasmablastic B-cell lymphoma, and comprises <1% of lymphomas. Advanced-stage presentation is typical; so few cases have been reported that there is limited information on outcomes, though short median survival of less than 12 months is reported.
Plasmablastic lymphoma (PBL) is seen as diffuse proliferations of immunoblastic appearing cells and has the immunophenotype of plasma cells. Originally thought to involve predominantly the oral cavity, it is now appreciated to also involve other extranodal sites. It is uncommon and mainly seen in HIV-infected males. The tumor has a high proliferation rate. The presence of EBV by EBER can help establish the diagnosis. CD20 expression is generally weak. The clinical course is aggressive. Occasional patients have long-term survival. Some physicians have used abbreviated cycles of EPOCH chemotherapy with involved field radiotherapy for limited disease with encouraging results, though the data are anecdotal.
Large B-Cell lymphoma arising in HHV8-associated multicentric Castleman disease is usually associated with HIV infection; the cells have appearance of plasma cells, and should be distinguished from PBL. Other HHV-8-associated neoplasms are sometimes seen (e.g., Kaposi sarcoma) at presentation.
PEL is a viral associated tumor (HHV-8) and presents mainly as serous effusions in the body cavities and is associated with HIV infection. All the tumor cells contain HHV-8 in 100% of cases and in 70% of cases are also EBV positive. Generally B-cell markers are absent, though they express CD45, and may express CD30. Immunoglobulin genes are clonally rearranged and hypermutated. Occasional patients have good outcome, but in general the prognosis is very poor.
Burkitt Lymphoma
BL is a rapidly growing lymphoma often involving extranodal sites and can present as an acute leukemia. The “starry sky” pattern on histopathology examination results from macrophages that have injected the apoptotic tumor cells. The endemic form found in equatorial Africa is generally EBV associated and is the most common childhood tumor there. The sporadic type represents 1% to 2% of lymphomas in developed countries. Immunodeficiency-associated BL is seen primarily in those with HIV infection, and can be the initial AIDS-defining condition. Short course intensive chemotherapy with rituximab is generally recommended (for adults), and cure rates are quite high for standard-risk disease. Poor-risk features (involvement of bone marrow, CNS, tumor mass >10 cm, and high serum LDH) do not rule out curative intent, but this outcome may be achieved in only 60% of such patients. Preliminary data suggests that dose-adjusted EPOCH-R chemotherapy (given with additional rituximab doses) is very effective in BL and a national clinical trial is being undertaken to better define this regimen for BL.
B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma
As the name suggests these aggressive tumors have morphologic features of both DLBCL and BL. Extranodal and leukemic presentation may occur along with mass lesions. CD19, CD20, CD22 are positive. BCL2 positivity in a case that would otherwise be classified as BL suggests a double hit lymphoma with both MYC and BCL2 translocations. The cellular proliferation is high. The standard of care is not established, but outcome with R-CHOP is reportedly poor.
Mature T- and NK-Cell Neoplasms
T-Cell Prolymphocytic Leukemia
The median age is 65 years and T-cell prolymphocytic leukemia (T-PLL) comprises <2% of mature lymphocytic leukemia. HTLV-1 is negative. Therapeutics includes alemtuzumab and allogeneic stem cell transplant. These are reported to benefit selected patients, but 3-year OSs are less than 30%.
T-Cell Large Granular Lymphocytic Leukemia
T-cell large granular lymphocytic leukemia (T-LGL) generally presents with a history of persistent, increased peripheral blood large granular lymphocytes of uncertain cause. Most cases are in those over 40 years of age, but the disease is rare (<2% of mature lymphocytic leukemia). It is important to distinguish T-LGL from a restricted clonal proliferation that sometimes occurs following allogeneic hematopoietic cell transplant. An indolent course is typical. Severe neutropenia is frequent, though thrombocytopenia is not generally seen. Along with the association of inflammatory comorbid conditions, immunophenotype suggests a chronic antigen-driven process and informs the use of immunosuppressive therapy for T-LGL.
Chronic Lymphoproliferative Disorders of NK Cells
Characterized by >6 months increased peripheral blood NK cells without a clear etiology, this rare condition presents equally in both genders with a median age of 60 years. The course is indolent in most cases. Spontaneous remission or aggressive transformation can occur.
Aggressive NK-Cell Leukemia
Nearly always EBV associated, with a median age of 42 years of age, it affects Asian ethnic groups predominantly. The immunophenotype is identical to that of extranodal NK/T-cell lymphoma except that CD16 is frequently positive.
Epstein Barr Virus-positive T-Cell Lymphoproliferative Disorders of Childhood
Two forms occur. The systemic form is a life-threatening clonal proliferation of EBV-infected T-cells that occurs shortly after primary acute EBV infection or in the setting of chronic active EBV infection. Rapid progression with multi-organ failure ensues over days to weeks. The hydroa vacciniforme-like lymphoma is a cutaneous T-cell lymphoma (CTCL) occurring in children and is associated with sun sensitivity. After a period of recurrent skin lesions over a period of up to 15 years, a more aggressive systemic progression may occur.
Adult T-Cell Leukemia/Lymphoma
Caused by the human retrovirus HTLV-1, ATLL is endemic in Southwestern Japan, the Caribbean basin, and parts of Central Africa where HTLV-1 prevalence is high. There are several clinical variants: acute, lymphomatous, chronic, and smoldering. The most common is the acute form with elevated white blood count, skin rash, lymphadenopathy, and hypercalcemia. Treatment with zidovudine and interferon-α (IFN-α) may prolong survival, but survival remains poor at a median of 9 months. Recent retrospective analysis supports using chemotherapy in sequence with zidovudine/IFN-α. Of interest, HTLV-1 also causes non-hematologic disease: tropical spastic paraparesis (TSP), also known as HTLVassociated myelopathy or chronic progressive myelopathy. HTLV-1 infection of the spinal cord results in paraparesis and weakness of the legs.
Extranodal NK/T-Cell Lymphoma, Nasal Type
This extranodal, often EBV-associated lymphoma results in vascular damage and often shows a cytotoxic T-cell phenotype (hence the NK/T designation). Upper aerodigestive involvement is characteristic, though it can involve other areas of the body. Nodular skin lesions, perforating intestinal lesions, or other sites are also seen. Prognosis is variable, but may be improved with upfront combination chemoradiotherapy. Bone marrow transplantation may be curative in selected patients.
Enteropathy-associated T-Cell Lymphoma
This is an intestinal lymphoma (mainly of the jejunum or ileum) composed of large lymphoid cells with an inflammatory background. It appears to be associated with celiac disease; early prevention with gluten-free diet appears to protect against lymphoma. There is a monomorphic variant occurring in regions where celiac disease is rare, and this is probably a different disease entity. Once lymphoma has developed, there is poor response to therapy and prognosis is unfavorable.
Hepatosplenic T-Cell Lymphoma
The T-cells of this extranodal and systemic lymphoma are generally derived from the γδ T-cell receptor type. The peak incidence is in adolescents and young adults and accounts for <1% of all lymphomas. There is an association with long-term iatrogenic immunosuppression. Initial response to chemotherapy is followed by relapse and median survival is generally less than 2 years.
Subcutaneous Panniculitis-like T-Cell Lymphoma
The median age with respect to subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is 35 years, and up 20% may have associated autoimmune disease, such as systemic lupus erythematosus. Patients often present with multiple subcutaneous nodules, particularly in the extremities and trunk. Cytopenias and elevated liver function tests are common. The neoplastic cells are usually CD8-positive.
They express βF1 and are negative for CD56: this finding helps distinguish from subcutaneous γδ T-cell lymphoma (which has a worse prognosis). If hemophagocytic syndrome develops, prognosis is poor. Otherwise, 80% survive 5 years or longer. Combination chemotherapy is used, but reports of immune suppressive therapy alone suggest activity and may help in treatment choices.
Mycosis Fungoides
Mycosis fungoides (MF) is a primary CTCL indicating the classical presentation of evolving skin patches, plaques, and tumors or the variants that show a similarly evolving clinical course. It accounts for 50% of CTCL. There is a wide age range, but most are older adults. In advanced disease, nodal, organ, and bone marrow involvement may be seen. The indolent clinical course slowly progresses over years to decades. Clinically it is staged I–IV. Disease confined to the skin with no lymph nodes is stage I and when there is a high blood Sézary cell count of >10,000/μL and or extensive lymph node involvement it is stage IV. Stage II has some lymph node involvement and stage III has skin erythroderma with or without lymph node and/or low Sézary cell count. Traditionally Sézary syndrome (SS) has referred to the leukemic form (see below). Early-stage disease does not benefit from multi-agent chemotherapy, and dermatologic skin-directed therapy is generally most appropriate.
Sézary Syndrome
SS is defined by the triad of erythroderma, generalized lymphadenopathy, and the presence of clonally related neoplastic T-cells with cerebriform nuclei (Sézary cells) in skin, lymph nodes, and peripheral blood. In addition, the absolute Sézary count must be >1,000/μL, there must be an expanded CD4+ T-cell population resulting in CD4/CD8 ratio of more than 10 and/or loss of one or more T-cell antigens. This is an aggressive disease with less than 20% survival at 5 years. Patients often succumb to opportunistic infections.
Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorders
Primary cutaneous CD30-positive T-cell lymphoproliferative disorders (PCALCL) account for 30% of CTCL; types are primary cutaneous anaplastic large lymphoma (C-ALCL), lymphoid papulosis (LyP), and borderline cases (where clear distinction between C-ALCL and LyP is not possible). Though prognosis is favorable, systemic lymphoma may develop, thus warranting ongoing surveillance. In PCALCL, surgical excision and radiotherapy are most commonly used for solitary tumors, whereas chemotherapy is given for multifocal disease. UV light phototherapy and low-dose methotrexate are commonly used therapies for LyP. There is interest in using the CD30-directed monoclonal immunoconjugate brentuximab vedotin for these tumors.
Primary Cutaneous Peripheral T-Cell Lymphomas, Rare Subtypes
These include the primary cutaneous γδ T-cell lymphoma with activated γδ T-cells having a cytotoxic phenotype and the CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, both with an aggressive course; the CD4-positive small/medium T-cell types have a more favorable prognosis with 80% survival at 5 years.
Peripheral T-Cell Lymphoma, Not Otherwise Specified
These account for about 30% of peripheral T-cell tumors in the Western world and are seen mainly in adults, with a male: female ratio of 2:1. Lymph node involvement is typical, but any site can be affected, including peripheral blood. Most patients present with advanced disease and B symptoms. CD30 expression is found in some cases. A variant, lymphoepitheliod (Lennert lymphoma) can be admixed with inflammatory and EBV+ Reed-Sternberg-like cells. The follicular variant can appear similar to nodular lymphocyte-predominant Hodgkin lymphoma while the T-zone variant can be mistaken for benign hyperplasia. Owing to CD30 expression, there is interest in brentuximab vedotin therapeutically.
Angioimmunoblastic T-Cell Lymphoma
Angioimmunoblastic T-cell lymphoma (AITL) occurs in middle age and in the elderly, and accounts for 15% to 20% of peripheral T-cell lymphomas. It is nearly always EBV associated, though the neoplastic cells are EBV negative. Generally AITL presents with generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. Pruritic skin rash is common. Effusions, arthritis, circulating immune complexes, hemolytic anemia and EBV-positive B-cell expansion are common. Median survival is <3 years. The associated immune dysfunction renders aggressive chemotherapy administration infeasible in many cases. GEP suggests deregulation of vascular endothelial growth factor as part of the pathogenesis, and has created interest in targeting this pathway therapeutically.
Anaplastic Large Cell Lymphoma , ALK-Positive
Anaplastic large cell lymphoma (ALCL), ALK-positive, is a CD30+ T-cell lymphoma that has a translocation involving the anaplastic lymphoma kinase (ALK) gene and expression of the ALK protein. It is important to distinguish this tumor from primary cutaneous ALCL and other lymphomas with anaplastic features. ALCL, ALK+ accounts for about 3% of adult and up to 20% of childhood lymphomas. Most cases present with advanced-stage disease with peripheral and/or abdominal adenopathy and bone marrow infiltration. High fevers are common. These tumors have a better prognosis than the ALCL, ALK-negative counterpart. The overall 5-year survival is about 80% with standard CHOP chemotherapy. Brentuximab vedotin is approved for relapsed ALCL.
Anaplastic Large Cell Lymphoma, ALK-Negative
Morphologically similar to ALCL, ALK+ and also CD30+, but lacking ALK protein expression, this entity was given a provisional categorization in the 2008 WHO classification system. The ALK-negative occurs mainly in adults over 40 years of age, and has a poorer prognosis compared to the ALCL, ALK+. Less than 20% OS at 5 years is expected. Brentuximab vedotin is approved for relapsed ALCL.
Hodgkin Lymphoma
Hodgkin lymphoma is covered in Chapter 20.
Immunodeficiency-associated Lymphoproliferative Disorders
Lymphoproliferative Disease Associated with Primary Immune Disorders
The most common lymphoproliferative disease (LPD) in this setting are ataxia telangiectasia, Wiskott-Aldrich syndrome, common variable immunodeficiency (CVID), severe combined immunodeficiency, X-linked lymphoproliferative disorder, Nijmegen breakage syndrome, hyper IgM syndrome, and autoimmune lymphoproliferative syndrome. In addition to LPD, other neoplasms occur at high rates in affected persons. Except for CVID, children are affected most. EBV is frequently involved.
Lymphomas Associated with HIV Infection
DLBCL (including primary brain), Burkitt, PEL, and PBL are AIDS-indicator conditions in those with HIV infection. Since the advent of cART, there has been a marked epidemiologic shift in the occurrence and outcomes of these tumors. Rituximab-based chemotherapy is the standard for DLBCL and Burkitt. Many experts recommend R-EPOCH in this setting. CHOP should not be used for HIV-Burkitt. Primary brain lymphoma (PCNSL) is rarely seen in the cART era. However, delays in diagnosis impair outcome. The standard diagnostic algorithm for HIV-PCNSL established early in the AIDS epidemic is no longer justified. Mass brain lesions should be approached in this population with the same degree of urgency and using the same diagnostic wherewithal as used in the HIV-unrelated setting, especially in patients likely to respond to cART. In particular, empiric antibiotic therapy to assess treatment failure as a means of establishing a malignant diagnosis should be relegated to the history books. When surgical biopsy is not feasible, CSF should be assessed for EBV by PCR in conjunction with FDG-PET of the brain. If both tests are positive, the positive predictive value for lymphoma is 100%, and specific therapy can be commenced. Patients with advanced HIV disease not amenable to treatment because of resistant HIV are becoming rarer with improvement in HIV therapeutics. Thus, if palliative approaches are deemed most appropriate based on the underlying HIV, it is essential to obtain expert HIV assessment in order to justify this decision.
Post-transplant Lymphoproliferative Disorders
These occur after solid organ or hematopoietic cell transplant. There is a range of pathology from those that are EBV-driven polyclonal proliferations (the majority of cases) to those that are EBV-positive or EBV-negative B- and T-cell lymphomas similar to those seen in the immunocompetent setting.
Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders
These LPD arise in patients treated with immunosuppressive drugs and appear as a spectrum from polymorphic proliferations as seen in PTLD at one end to DLBCL at the other end of the spectrum. EBV is variably associated depending on the underlying cause for iatrogenic immune suppression and the LPD presentation itself.
CLINICAL MANAGEMENT
Staging
Pretreatment staging evaluation for systemic NHL follows.
III. Viral testing if indicated by risk or lymphoma subtype
VII. Bone marrow biopsy
VIII. Lumbar puncture with cytology should be performed in patients at risk for CNS disease:
The Ann Arbor Staging System, initially developed for patients with Hodgkin lymphoma, is used in NHL. This system does not apply to lymphoblastic leukemia/lymphoma or to MF (Table 16.6).
Posttherapy Restaging for Response Evaluation
At completion of therapy, repeat all restaging studies. Generally restaging after four cycles is indicated in aggressive lymphomas (repeat all abnormal tests). In indolent lymphomas, response to therapy may be slower; restaging can be performed less frequently. The rate of response may reflect tumor sensitivity to treatment and may have prognostic value. However, early PET in DLBCL has not consistently been shown to predict survival. Other novel imaging methods of interest include diffusion-weighted MRI scanning and may yield similar early response characteristics as FDG-PET.
Disease progression or no response implies extremely poor prognosis. Biopsy of residual masses after therapy may be required to determine whether viable tumor is present. Routine PET surveillance is not recommended after completion of treatment restaging has been performed.
PROGNOSTIC FEATURES
Prognostic features are related to disease and to the individual patient. Disease-related features include tumor bulk, stage, number of extranodal disease sites, and histologic type and tumor histogenesis (or tumor biology). Patient-related factors include age and performance status, and whether or not there are comorbid conditions present that may affect ability to administer therapy.
Prognostic assessment and modeling strategies have been developed to predict the outcome based on clinical presentation. The most commonly used model is IPI (Table 16.6). The IPI was initially developed for aggressive NHL, but is applicable or has been adapted to other NHL subtypes. For example (Table 16.7), the follicular IPI (FLIPI) and the mantle cell IPI (MIPI) are adaptations of the IPI and have prognostic value for the respective histologic NHL types (Table 16.8). In the IPI, 1 point is assigned for each of the following:
Age
For IPI and FLIPI age over 60, 1 point
For MIPI, 1 point for age 50 to 59, 2 points for age 60 to 69, 3 points for age ≥ 70
Eastern Cooperative Oncology Group (ECOG) performance status 2 or more
For IPI, 1 point
For MIPI, 2 points
LDH above normal
For IPI and FLIPI, 1 point
For MIPI 0.67 to 0.99 1 point; 1.0−1.49, 2 points, ≥1.5, 3 points
Extranodal sites
For IPI, two or more, 1 point
For FLIPI, more than four, 1 point
Stage III or IV disease
For IPI and FLIPI, 1 point
Hemoglobin level
For FLIPI < 120 g/L, 1 point
WBC, 106/L
For MIPI 6.7–9.999, 1 point; 1.0–14,999, 2 points; ≥15,000, 3 points
Based on adding points from the various clinical characteristics, risk can be assigned. In age-adjusted IPI for patients younger than 60 years of age, 1 point each is assigned for
Performance status 2 or more
LDH above normal
Stage III or stage IV disease
In ARL, the primary prognostic determinant has traditionally been the CD4 cell count. However, among those whose HIV is sensitive to cART, the IPI and lymphoma-specific features appear to be of relatively greater prognostic importance. Low CD4 cell count alone does not confer poorer outcome to curative intent therapy. However, very low CD4 cell count increases the risk of death due to other AIDS-related causes and unless the patient has an increase in CD4 cells, this risk persists after successful completion of lymphoma therapy.
TREATMENT PRINCIPLES
Treatment of NHL is guided by clinical behavior, and this is in large part dependent on the specific disease entity. Clinical behavior is generally described as indolent, aggressive, or highly aggressive. Conventional treatment now includes chemotherapy, radiotherapy, immunotherapy, or a combination of these modalities. Novel treatments, including immunoconjugates, immune modulators, and molecularly targeted agents are now in everyday practice or the subject of current investigations. Ongoing clinical research will refine how newer treatments are used and combined to augment or supplant current standards of care.
Principles of Therapy: Indolent B-Cell and T-Cell Lymphomas
The natural history is one of a relatively slow-growing lymphoma with low potential for cure but with median survival measured in years to decades. For disseminated symptomatic disease, many experts recommend single agent rituximab or rituximab combined with CHOP or bendamustine. ASCT increases complete responses but not cure. Maintenance rituximab improves PFS. Other approaches that may also be used in patients with disease progression include fludarabine (combined with rituximab and or mitoxantrone or cyclophosphamide) and yttrium 90 ibritumomab tiuxetan radioimmunotherapy. Novel agents such as lenalidomide are of interest. Grade 3B lymphomas are often treated differently than the other grades, using therapy as in DLBCL. FL can progress with transformation to a DLBCL, and this nearly always requires treatment. Generally the prognosis is poor after transformation. See the section on DLBCL for treatment of transformed disease.
Individual prognostic features must be considered in treatment planning. Those with the most favorable prognosis may benefit less from early therapy whereas those with poorer prognosis may derive greater benefit from early therapy. It is important to consider whether the planned therapy will improve or detract from a patient’s well-being. If the toxicity of therapy creates symptoms where there are none, watchful waiting may be a better strategy.
Rituximab as a single agent in previously untreated FL yields up to 75% RRs. Maintenance rituximab may prolong remission (at 3 years of median follow-up, duration of remission was 23 versus 12 months, favoring rituximab maintenance group receiving 375 mg/m2 every 2 months for 4 doses post induction). As a single agent in previously treated FL, rituximab can yield responses in 50% to 60% of cases, with median response duration of 6 to 16 months. Rituximab with CHOP induces complete responses in up to 95% of previously untreated FLs with a median response duration not reached at 50 months of follow-up. Rituximab combined with fludarabine yields results similar to CHOP plus rituximab (though fludarabine is profoundly immunosuppressive). Rituximab combined with bendamustine has been reported to have superior RR, PFS, and less toxicity compared to CHOP combined with rituximab, though these findings have as yet not been reported in peer review form.8,9 Following initial therapy, 2 years of rituximab maintenance may improve PFS. Additionally, some advocate use of radioimmunotherapy for initial disease, utilizing 131I-tositumomab. Radioimmunotherapy for relapsed disease includes yttrium 90-ibritumomab tiuxetan (Zevalin), which is Food and Drug Administration (FDA)-approved and well tolerated. In a randomized trial, Zevalin resulted in statistically and marginally clinically significant higher objective response rate (ORR) and complete response (CR) but not response duration compared with rituximab alone in relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Tositumomab and iodine-131 tositumomab (Bexxar) are approved by the FDA for the treatment of patients with CD20-positive, follicular NHL, in cases with and without transformation, when disease is refractory to rituximab and has relapsed after chemotherapy. Thus, there are a substantial number of therapeutic choices (Table 16.9).
Indolent stage I B-cell lymphomas may be curable with 10-year disease-free survival (DFS) of approximately 50% with radiation alone. Because of the long natural history, this is a difficult disease to study. For example, a large phase II trial of more than 100 patients was initiated in 1984 but was not completed and published until 2003. A 10-year DFS of 76% was reported, suggesting that combined radiation and chemotherapy may be superior to radiotherapy alone in stage I and II disease. Large retrospective databases indicate that the observational strategy does not compromise survival compared to early intervention.
For CLL/small lymphocytic lymphoma treatment options include bendamustine, fludarabine, and rituximab, given concurrently or sequentially. Alemtuzumab is approved for fludarabine-refractory disease, with RRs of approximately 30%. Cladribine may also be used. Novel therapeutics with agents such as PI3Kδ inhibitors, lenalidomide, and Bruton tyrosine kinase inhibition may transform therapy for this disease in the future.
For lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia treatment options include conventional therapies with alkylating agents (especially chlorambucil), with or without corticosteroids. CHOP is sometimes used as well. Purine analogues such as fludarabine or cladribine are also active. RR to first-line therapy ranges from 38% to 85%. RR to fludarabine in previously treated patients ranges from 30% to 50%. Initial therapy with rituximab has produced overall RRs of 20% to 40%, with risk of IgM paraprotein flare. Preliminary data suggests a role for agents such as alemtuzumab, bortezomib. There is interest in thalidomide and analogs, particularly lenalidomide and pomalidomide.
For marginal zone lymphoma effective eradication of H. pylori infection can result in lymphoma regression and likely cure, a finding that strongly supports this bacterial etiology of the tumor. When associated with autoimmune disease (such as Sjögren syndrome or Hashimoto thyroiditis), chemotherapy with or without rituximab may be useful. Local therapy such as surgery or regional irradiation may yield relatively long-term disease control. Splenectomy may be indicated for splenic marginal zone lymphoma. Cases associated with HCV infection may regress with effective HCV therapy.
Principles of Therapy: Aggressive B-Cell Lymphomas
Mantle Cell Lymphoma
Most patients with MCL present with advanced-stage disease. Unlike other aggressive lymphomas, it is incurable and has a short median survival of approximately 6 years. The blastic variant may be more aggressive with a propensity for CNS involvement (25%) and shorter survival. There may be a survival advantage in younger patients with stage IA or IIA treated with radiation therapy. Therapy with rituximab-based CHOP or more intensive regimens such as the Hyper-CVAD regimen are used, sometimes followed with autologous bone marrow transplantation. Large cooperative group studies generally have not confirmed the more intensive therapy to benefit the general population with MCL as many subjects were unable to complete the planned therapy. Bortezomib is approved for treatment of relapsed MCL. Molecular targeted therapies, including mTOR inhibitors, and immune modulator drugs (e.g., lenalidomide) are of interest.
Diffuse Large B-Cell Lymphoma
R-CHOP is the standard of care for curative intent in DLBCL (Table 16.10). For most CD20+ lymphomas, addition of rituximab improves the outcome, and this is certainly the case for DLBCL in which rituximab improves the cure rate.2 For localized disease, many experts recommend limited cycles of chemotherapy combined with involved field radiotherapy. Owing to late toxicity and recurrent disease, the OS benefit of this approach is not clear. Salvage therapy following relapse is most effective for those whose disease remains chemotherapy sensitive. Following treatment with regimens such as rituximab, ifosfamide, carboplatin, and etoposide, ASCT offers curative potential for approximately 50% of patients. However, in the rituximab era, patients relapsing within 12 months after initial R-CHOP therapy appear to represent a particularly poor prognostic group. Median event-free survival following ASCT may be less than 12 months for this group.
Probability of cure with initial therapy can be estimated using prognostic models, such as the IPI. Addition of rituximab to CHOP appears to “equalize” various regimens to some extent. For example, the advantage of CHOEP (etoposide added to CHOP) over CHOP alone in young patients is no longer seen when rituximab is added to either regimen.
For stage I to II disease, three cycles of CHOP plus involved-field radiotherapy results in 5-year PFS of 77% and OS of 82%, better than with 8 cycles of CHOP alone (64% and 72%, respectively). However, R-CHOP now is commonly used in early-stage disease without radiation.
In advanced-stage disease, the OS and PFS are approximately 50% and 32%, respectively, at 5 years with CHOP. Randomized trials show that addition of rituximab on day 1 of each cycle of CHOP or CHOP-like cycle resulted in improved event-free survival, PFS, and OS in all patient groups. Maintenance rituximab therapy in DLBCL shows no clear advantage when rituximab is administered concomitantly with chemotherapy. Possible alternatives to R-CHOP as front-line therapy, or as salvage therapy are listed in Table 16.11.
For HIV-associated DLBCL, an underpowered randomized trial of CHOP versus R-CHOP was reported; there was no rituximab benefit in these patients owing to increased infection-related death. However, excess infection was restricted to those with CD4 cells under 50/mm3. Most experts recommend all HIV+ patients receive rituximab if curative intent therapy is planned. Antibiotic prophylaxis is recommended for those with low CD4 cell counts. A randomized phase II trial of R-EPOCH compared to EPOCH followed by rituximab favored concomitant R-EPOCH, and this is a standard of care recommended by many experts treating AIDS-related lymphoma.
TREATMENT PRINCIPLES: HIGHLY AGGRESSIVE B-CELL LYMPHOMA
Burkitt Lymphoma/B-Cell ALL
Intensive short duration therapy forms the basic treatment strategy for curative intent (Table 16.12). Treatment may provoke tumor lysis syndrome and prophylaxis should be used: alkalinize the urine with D5W plus 100 mEq sodium acetate at 100 to 150 mL/h, add allopurinol, 600 mg, orally daily for 2 days, then 300 mg/day orally until resolution of the tumor lysis syndrome. Aggressive chemotherapy is potentially curative in these tumors. For adults, rituximab is now considered a standard part of the treatment. This has not yet been shown to benefit children. For adults, randomized trials have not informed therapy. The CODOX-M/IVAC risk-stratified regimen is based on phase II data.5,6The regimen consists of three cycles of CODOX-M for low-risk disease (Tables 16.13 to 16.15). (All of the following: normal LDH, WHO performance status 0 or 1, Ann Arbor stage I to II, and no tumor mass 10 cm or larger). For high-risk disease (e.g., do not meet criteria for low risk) four cycles of alternating CODOX-M and IVAC are used. An alternative approach is the hyper-CVAD regimen with addition of rituximab.4 Additionally, preliminary data suggest EPOCH-R is effective in BL. As yet there is no sufficient data to recommend this treatment routinely outside of a research protocol, but favorable toxicity profile may justify use if a given patient cannot tolerate more established aggressive dose-intensive therapy. The dose-adjusted EPOCH-R regimen is the focus of a national clinical trial to define its efficacy in Burkitt and C-MYCpositive DLBCL.
Treatment of Recurrent and Refractory B-Cell Lymphoma
Many patients with NHL require additional therapy because of disease recurrence or refractoriness to therapy. Although grades I and II FL are not curable, high-dose chemotherapy followed by autologous transplant improves PFS. In aggressive NHL, approximately 40% to 50% of patients fail to achieve remission with conventional chemotherapy. Among those who do achieve a CR, 30% to 40% will relapse. These patients may benefit from salvage therapy (see Table 16.11).3
Principles of Salvage Therapy
Conventional wisdom promotes the use of non–cross-resistant chemotherapy such as (cisplatin, cytarabine, and dexamethasone), ESHAP (etoposide, methyl prednisolone, cytarabine, and cisplatin), and ICE (ifosfamide, carboplatin, etoposide). However, evolving understanding of cellular apoptotic response to chemotherapeutic stimuli suggests that true non–cross-resistance drugs may not exist—as mechanisms for tumor resistance may not be entirely drug-specific—because of the intrinsic high apoptosis thresholds in refractory tumors. Both in vitro and empiric clinical data provide evidence that tumor resistance can be overcome by using drugs already administered, but with different infusion schedules (e.g., by prolonged infusion regimens such as dose-adjusted EPOCH-R). In addition, other agents such as in ICE or ESHAP have also shown utility in the setting of relapsed and refractory NHL.
High-dose chemotherapy and ASCT may confer curative advantage in some patients whose disease is responsive to salvage chemotherapy. ASCT achieves long-term survival in up to 50% of patients with chemotherapy-sensitive relapsed DLBCL, and some prospective randomized studies have documented the superiority of ASCT over salvage chemotherapy for relapsed DLBCL. Patients with low-risk IPI are most likely to benefit. However, in the rituximab era, those that do relapse following rituximab-inclusive therapy appear to be selected for the poorest-prognosis patients, and salvage is less successful in many cases owing to this.
Allogeneic transplantation remains investigational. Nonmyeloablative or reduced intensity stem cell transplantation (RIST) attempts to exert immunologic effects against the tumor without the risk of high-dose chemotherapy. High-dose chemotherapy does not appear to overcome tumor resistance in the majority of cases. Graft engineering to enhance graft-versus lymphoma benefit and to decrease graft-versus-host complications remains an active area of investigation. Studies have not consistently shown strong graft-versus-lymphoma effects in the majority of patients.
Patients with well-controlled HIV with relapsed NHL should not be routinely excluded from consideration for ASCT.
Acquired Immune Deficiency Syndrome-related Lymphoma (Systemic) Treatment Considerations
In the current era of effective cART for HIV infection, most HIV-infected patients with lymphoma should be treated similar to their HIV-unrelated counterparts. One exception is that some experts recommend CNS prophylaxis for all systemic ARL (Table 16.16). Prior to cART, low-dose chemotherapy was recommended for HIV-infected patients. This should rarely, if ever, be used in the current era. Possible exceptions may be considered for patients who have advanced AIDS with essentially untreatable HIV infection. Standard-dose chemotherapy has supplanted low-dose therapy in the CART era. See the sections above on DLBCL and Burkitt for therapy. Phase II data support use of EPOCH-R and CODOX/M-IVAC in HIV-infected patients.7
The use of concurrent CART is unsettled. There are inadequate data to make evidence-based recommendations. With currently available cART, it should be possible to avoid clinically apparent toxicity when combining lymphoma and HIV therapy. However, there is a possibility for clinically subtle yet important pharmacokinetic interactions when cART and anticancer therapeutics are combined. For example, ritonavir appears to increase toxicity associated with vinka alkaloids through the cytochrome P450 3A4 metabolic pathway. This can result in decreasing doses of cancer agents and possibly undermining curative potential of the regimen. Certainly a case can be made to suspend cART for some patients. For example, a patient with Burkitt and tumor lysis syndrome should be started on definitive Burkitt therapy and cART can wait until the patient’s physiological condition permits consideration of administering lifelong chronic disease HIV therapy. Many oncologists recommend continuing CART if a patient is already on a stable well-tolerated regimen, but delaying its initiation until after lymphoma therapy in those who are not.
T-Cell Lymphoma:Treatment Principles
T-cell lymphomas tend to have a poorer PFS and OS than aggressive B-cell lymphomas. Systemic ALCL is an exception and is among the most curable subtypes with doxorubicin-based treatment. Some T-cell subtypes have no potential for cure and should be approached palliatively, as in ATL and primary cutaneous anaplastic lymphoma. Other T-cell subtypes, including angioimmunoblastic and PTL, have low curative potential with conventional dose treatment and should be considered for trials targeting high-risk patients.
Corticosteroids, alkylating agents, and bexarotene are available for topical use and are frequently utilized. In addition to topical therapies, ultraviolet radiation, either UVA or UVB, and total skin electron beam therapy (TSEBT) are utilized in limited-stage CTCL. Psoralen combined with ultraviolet A (PUVA) is associated with a CR rate exceeding 90%, and a prolonged disease-free interval, in early-stage disease. For advanced-stage disease, bexarotene, denileukin difitiox, and more recently histone deacetylase inhibitors (vorinostat and romidepsin are FDA approved for this indication in previously treated patients) all have activity. Systemic multi-agent chemotherapy is of limited use and reserved primarily for patients with advanced disease which has recurred and are not responding following other interventions.
Approval of histone deacetylase inhibitors for previously treated CTCL has advanced systemic therapeutic approaches. Both vorinostat and romidepsin are agents in this class with activity in CTCL.
Adult T-Cell Leukemia/Lymphoma
ATLL cannot be cured. Ameliorative treatments include interferon and doxorubicin-based combination chemotherapy. Retrospective data suggests that sequential combination chemotherapy followed by zidovudine with IFN-α improves survival substantially.
References