This chapter addresses the following Geriatric Fellowship Curriculum Milestone: #22
The majority of lymphomas occur in older adults.
Modern classification systems for lymphomas are evolving rapidly and incorporate immunophenotyping and genetics.
Comorbidity and frailty are strong modifiers of prognosis and must be incorporated into treatment planning.
Immunotherapies play an increasing role in treatment of some lymphomas; consider life expectancy when planning treatment.
NON-HODGKIN AND HODGKIN LYMPHOMA: INTRODUCTION
The intimate interplay between the aging process and the development of malignancy in many ways ensures that cancer is a disease of older individuals and the lymphoid malignancies are no exception. The lymphoid malignancies comprise over 60 heterogeneous and complex entities as identified in the World Health Organization (WHO) classification 2008. The median age at diagnosis of representative entities such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are 64, 71, and 72 years, respectively. Consequently, the care of this patient population frequently requires the care of the older patient. In this chapter we focus on Non-Hodgkin lymphomas (NHLs) and Hodgkin lymphomas (HLs); acute leukemia and CLL/SLL are addressed in Chapter 104.
NHLs are the most common lymphoid malignancy, representing a heterogeneous group of lymphoproliferative disorders that originate from cells of the immune system, including B lymphocytes, T lymphocytes, or natural killer (NK) cells. In the United States, the B-cell lymphomas predominate, making up 80% to 85% of lymphoma diagnoses, with T-cell histologies representing 15% to 20% of the balance; NK-cell lymphomas are rare at less than 1%.
The spectrum of clinical presentations for lymphoma can be quite protean, dependent on the type of lymphoma, the disease subtype, each with variable disease courses, and the presence of nodal or extranodal involvement. Broadly speaking, lymphomas can be characterized as either indolent behaving with median survivals measured in decades or aggressive behaving, with life-threatening consequences in a matter of weeks or months if left untreated.
Indolent lymphomas are more often identified incidentally during routine physical examination or laboratory evaluation, particularly with increased reliance on routine blood testing and imaging in the modern era. Often, these entities present with slowly progressive lymphadenopathy, splenomegaly, and potential cytopenias from bone marrow involvement. Examples include the prototypic follicular lymphoma (FL), marginal zone lymphomas, and CLL/SLL.
In contrast, aggressive lymphomas are more likely to present with acute or subacute symptoms including a rapidly growing mass, systemic B symptoms (fevers, night sweats, weight loss), elevated serum lactate dehydrogenase, hypercalcemia, and hyperuricemia. Examples include DLBCL, peripheral T-cell lymphomas (PTCL), and Burkitt lymphoma (BL).
Clinical characteristics of NHLs include “B” symptoms, defined as fever greater than 38°C, unexplained weight loss greater than 10% of body weight over the past 6 months, and drenching night sweats. Up to 40% of patients with NHL may have B symptoms; more commonly evident in aggressive or biologically transformed disease (approaching 50%) than in low-grade lymphomas (< 25%). Less common presenting features can include skin rash, pruritus, fatigue, fever of unknown origin, effusions, and hypersensitivity to insect bites. Extranodal presentations occur in 10% to 35% of patients at initial diagnosis, with extranodal sites developing in approximately 50% of patients over the course of their disease. As lymphocytes naturally transit through blood and can be found in any tissue compartment, lymphomas have been reported in essentially all conceivable sites. Gastrointestinal involvement can be associated with anorexia, weight loss, nausea and vomiting, early satiety, abdominal pain, obstruction, and, rarely, perforation. The central nervous system can be involved primarily or secondarily, presenting with headache, lethargy, focal neurologic symptoms, seizures, paralysis, cranial neuropathies, and lymphomatous meningitis. Monoclonal serum proteins (M spike) can be associated with some lymphoma entities, more commonly marginal zone lymphomas, lymphoplasmacytic lymphomas, and Waldenström macroglobulinemia. Paraneoplastic phenomenon can also rarely be present and, at times, precede the diagnosis of lymphoma. Examples include hemolytic anemia, cryoglobulinemia, and idiopathic thrombocytopenia.
Based on the American Cancer Society data, in 2016, an estimated 81,080 individuals will be diagnosed with lymphoma in the United States, 72,580 NHL and 8,500 HL with 212270 individuals dying from a lymphoid malignancy (predominately NHLs, 20,150). To put this in perspective, NHL and HL together account for 5% and 4% of all new cancer diagnoses and 4% and 3% of all cancer deaths, in men and women, respectively.
Age-Related Incidence in the United States
From 2007 to 2011, incidence rates for HL were stable in both men and women, while rates for NHL slightly increased among men (0.3% per year) and were stable among women. Death rates for HL, however, have been decreasing for the past four decades; from 2007 to 2011, rates decreased by 2.2% per year among men and by 2.7% per year among women. Death rates for NHL began decreasing in the late 1990s with the advent of monoclonal antibody treatments, particularly rituximab, a chimeric anti-CD20 monoclonal antibody; from 2007 to 2011, rates decreased by 1.8% per year among men and by 2.9% per year among women. Declines in lymphoma death rates have reflected improvements in both supportive care and treatments over the decades.
The incidence of NHL in the United States had been increasing significantly from 1970 to 1995 with a slowing of the rise from the mid-1990s onward. Although a proportion of this increase is attributable to the human immunodeficiency virus (HIV) epidemic and the consequent increase in AIDS-related NHL, this does not account for the full picture. Rather, much of the increase in incidence is a likely consequence of the aging of the population, with the greatest increases noted in patients in their sixth and seventh decades. Increases in life-expectancy, baby-boomers entering late life, and decreases in mortality from other causes are all implicated. Attendant with this change in demographics, the United States is projected to witness increases in incidence of NHL by 67% and HL by 70% in older adults by the year 2030. This fact is evidenced as well by the increasing median age of individuals with NHL over the last two decades. Consequently, the interplay between aging biology, comorbidity and competing risks is ever more prevalent for the treating oncologist.
NHL CLASSIFICATION SYSTEM—WORLD HEALTH ORGANIZATION 2008
Increased Biological Basis
Historically, lymphoma classifications were based on the morphologic patterns of cell growth, including size and shape of tumor cells (Rappaport classification, 1956). However, with the discovery of distinct types of lymphocytes (B, T, and NK), this classification was replaced by the Kiel classification, dividing lymphomas into low and high grades on the basis of histologic features. These evolving concepts were further refined and unified in the International Working Formulation (IWF), which created three useful major categories of low, intermediate and high grade lymphomas, relying on both morphology and clinical behavior. Lack of reproducibility and of immunophenotyping hampered the IWF system.
Although lymphoma classification has remained a complicated endeavor, since the advent of the Revised European American Classification (REAL) classification in 1994 and the subsequent update by the World Health Organization (WHO) classification in 2001, lymphoma diagnosis has increasingly integrated cell of origin (B, T, NK), morphology, immunophenotype, genetic and clinical features to define disease. The REAL classification cohort comprised 1403 cases of NHL, identifying the 13 most common histologic subtypes in 90% of the cases in the United States. These included DLBCL, 31%; follicular lymphoma (FL), 22%; SLL/CLL, 6%; mantle cell lymphoma (MCL), 6%; peripheral T-cell lymphoma (PTCL), 6%; and mucosa-associated lymphoid tissue (MALT) lymphoma, 5%. Notably, in the United States over 50% of cases are classified as either DLBCL or FL, two entities that are paradigmatic in many ways of treatment approaches for the aggressive and indolent lymphomas, respectively.
Importantly, in 2008 the WHO classification (Table 105-1) has undergone further refinements, with new updates and the International T-cell lymphoma Project’s examination of 1314 cases of PTCL or NK/T-cell lymphomas lending greater clarity and complexity to these diagnoses. NK/T-cell lymphomas comprise 15% to 20% of all NHL diagnosis, with the most common subtypes being: PTCL not otherwise specified (NOS; 25.9%), angioimmunoblastic lymphoma (AILD; 18.5%), anaplastic large cell lymphoma (ALCL; 12.1%; ALK-positive 6.6% and ALK negative 5.5%), NKTCL (10.4%), and adult T-cell leukemia/lymphoma (ATLL; 9.6%). Furthermore, the 2008 updates more broadly integrated new diseases and subtypes identified in the past, affirmed the importance of detecting viral entities in some diagnoses (eg, EBV, HHV8, and HTLV1), as well as increased the use of genetic features in diagnosis, such as cytogenetics and fluorescent in situ hybridization (FISH) in defining specific NHL entities.
TABLE 105-12008 WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION ||Download (.pdf) TABLE 105-1 2008 WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION
|WHO Classification |
|Chronic lymphocytic leukemia/small lymphocytic lymphoma |
|B-cell prolymphocytic leukemia |
|Splenic marginal zone lymphoma |
|Hairy cell leukemia |
|Splenic lymphoma/leukemia, unclassifiable |
| Splenic diffuse red pulp small B-cell lymphoma* |
| Hairy cell leukemia-variant* |
|Lymphoplasmacytic lymphoma |
| Waldenström macroglobulinemia |
|Heavy chain diseases |
| α Heavy chain disease |
| γ Heavy chain disease |
| μ Heavy chain disease |
|Plasma cell myeloma |
|Solitary plasmacytoma of bone |
|Extraosseous plasmacytoma |
|Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) |
|Nodal marginal zone B-cell lymphoma (MZL) |
| Pediatric-type nodal MZL |
|Follicular lymphoma |
| Pediatric type follicular lymphoma |
|Primary cutaneous follicle center lymphoma |
|Mantle cell lymphoma |
|Diffuse large B-cell lymphoma (DLBCL), not otherwise specified |
| T-cell/histiocyte-rich large B-cell lymphoma |
| DLBCL associated with chronic inflammation |
| Epstein-Barr virus (EBV)+ DLBCL of older adults |
|Lymphomatoid granulomatosis |
|Primary mediastinal (thymic) large B-cell lymphoma |
|Intravascular large B-cell lymphoma |
|Primary cutaneous DLBCL, leg type |
|ALK+ large B-cell lymphoma |
|Plasmablastic lymphoma |
|Primary effusion lymphoma |
|Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease |
|Burkitt lymphoma |
|B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma |
|B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic |
|Hodgkin lymphoma |
|Hodgkin Lymphoma |
|Nodular lymphocyte-predominant Hodgkin lymphoma |
|Classic Hodgkin lymphoma |
| Nodular sclerosis classic Hodgkin lymphoma |
| Lymphocyte-rich classic Hodgkin lymphoma |
| Mixed cellularity classic Hodgkin lymphoma |
| Lymphocyte-depleted classic Hodgkin lymphoma |
For the majority of lymphomas, despite an increasing understanding of biology, the cause remains unknown. Stochastic mutational events inherent in the normal cell division process of lymphocytes are expected to result in a continuous random event rate. Epidemiologic studies have indicated increased incidences associated with a personal family history of lymphoma, past radiation or chemotherapy treatment, immunosuppressive agents, smoking, and obesity. Environmental exposures to agricultural pesticides accounted for an increased incidence of lymphoma in central United States, hair dyes (prior to the 1980s), agent orange and other dioxins. Dysregulation of the immune system may precede a lymphoma diagnosis, with increased risk associated with autoimmune diseases (eg, rheumatoid arthritis, lupus, Sjögren syndrome, Hashimoto thyroiditis), solid organ transplantation, and celiac sprue. A number of infections have also been implicated in the pathogenesis of lymphomas, either as a consequence of immune dysregulation or chronic antigenic drive. Associations clearly exist with human immunodeficiency virus (HIV), human T lymphoma atrophic virus type I (HTLV-I), Epstein-Barr virus (EBV), hepatitis C, hepatitis B virus, Helicobacter pylori, and human herpesvirus 8 (HHV8).
EBV in Lymphoma and Older Adults
In the most recent WHO classification iteration of 2008, a provisional entity termed EBV (+) DLBCL of older adults was defined, consisting of an EBV-positive monoclonal large B-cell proliferation in patients older than 50 years, median age approximately 70 years, with no known history of immunodeficiency. Most patients have an ABC phenotype, strong NF-κβ activation, increased extranodal distribution at diagnosis, and inferior survival. Optimal treatment strategies are not defined.
EBV has also been implicated in the pathogenesis and outcome of HL, with a negative impact on outcome in advanced age as distinct from younger patients. Nasal NK/T-cell NHL, primary CNS lymphoma, and EBV-associated PTLD.
NHLs are frequently characterized by balanced translocations, resulting in functional fusions that confer a survival advantage for the affected cell population (Table 105-2). Such translocations often involve the immunoglobulin heavy chain region on chromosome 14, leading to constitutive activation of the translocated partner and consequently to increased signaling for the translocated gene, such as the antiapoptotic pathways (BCL2), cell cycle proteins (CCND1), and cellular proliferation (cMYC).
TABLE 105-2LYMPHOMAS WITH KNOWN TRANSLOCATIONS ||Download (.pdf) TABLE 105-2 LYMPHOMAS WITH KNOWN TRANSLOCATIONS
|LYMPHOMA HISTOLOGY ||COMMON TRANSLOCATION ||GENE PARTNERS |
|Mucosa-associated lymphoid tissue lymphoma ||T(11;18)(q21;q21) ||AP12/MALT, BCL-10 |
|Mantle cell lymphoma ||T(11;14)(q13;q32) ||BCL-1, IgH |
|Follicular lymphoma ||T(14;18)(q32;q21) ||BCL-2, IgH |
|Diffuse large-cell lymphoma || |
|Burkitt lymphoma || |
|C-MYC, IGH |
|Anaplastic large-cell lymphoma ||T(2;5)(p23;q35) ||ALK |
|Lymphoplasmacytoid lymphoma ||(9;14)(p13; q32) ||PAX5, IgH |
Evaluation of a patient with suspected lymphoma includes a careful history and physical examination, with close attention to lymphatic sites including Waldeyer ring and the spleen. Extranodal sites of involvement to consider on examination include the skin, central nervous system abnormalities, testes, breasts, and bone. Standard blood work includes a CBC, comprehensive panel, calcium, uric acid, lactate dehydrogenase (LDH), serum protein electrophoresis, β2 microglobulin (indolent lymphomas), serologic testing for HIV, and hepatitis B and C.
A biopsy is required for diagnosis and classification of NHL and HL. Generally, an excisional or incisional lymph node biopsy is preferred given the requirements for increasingly complex pathologic diagnostic evaluations. These regularly include need for adequate morphologic assessment, immunohistochemical (IHC) staining, flow cytometry, FISH testing, cytogenetics, polymerase chain reaction (PCR) studies for clonality (immunoglobulin gene rearrangement studies for B-cell clonality, T-cell receptor gene rearrangements for T-cell lymphomas), and increasingly gene expression profiling (GEP). Fine-needle aspiration is often helpful as an initial discriminator between reactive adenopathy, carcinoma, and lymphoma. However, more definitive biopsy is generally required, particularly for an initial diagnostic procedure. Core biopsy can occasionally render sufficient material when excisional biopsy is not feasible. The site of biopsy should be determined based on integration of available information such as safety of the procedure, likely diagnostic yield, and representative sampling. Functional imaging (eg, positron emission tomography [PET] scan) is often beneficial at directing the site of biopsy when discordant fluorodeoxyglucose (FDG) avidity is present, with the most metabolically active lesions generally representing the most aggressive biology.
Originally developed in 1974 for HL, the Ann Arbor staging system was the equivalent of the TNM (tumor-lymph node-metastasis) staging system for lymphoid malignancies. This staging system defines disease location and extent and prognostic information, permitting cross-study comparisons, and establishes baseline disease extent to allow for response comparison. Modified in 1988, the Cotswold classification formally included CT scans and designations for bulky disease (X), dividing HL patients in four stages, with A and B subclassifications based on the absence or presence of B symptoms. Universally accepted response criteria in NHL and HL were published in 1999 by the NCI Working Group and revised in 2007 by the International Working Group (IWG) to incorporate PET and bone marrow immunohistochemistry (IHC)/flow in response assessment. This has formed the foundation for staging and response evaluations for NHL and HL over the last decades, acknowledging certain histologies have warranted their own staging and response assessment given varied clinical course (eg, CLL/SLL, Waldenström macroglobulinemia, cutaneous T-cell lymphoma).
Of note, in contrast to many solid tumors, it is important to realize stage alone is often a poor arbiter of outcome in NHL. Clinical and biologic prognostic models, generally including stage as one of the risk factors, are better predictors of outcome. For instance, it is instructive that a substantial number of DLBCL patients with advanced-stage III/IV disease will be cured, and for indolent lymphoma patients, stage IV disease is the norm, but survival is measured in decades.
Updated Lugano Classification 2015
A workshop held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland in June 2011 sought to modernize recommendations for evaluation, staging, and response assessment for patients with HL and NHL. Comprising leading international hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, this effort led to a revision of the IWG guidelines of 2007 as the published Lugano classification in 2014 (Table 105-3). The most salient changes included formal integration of PET scanning into initial staging for FDG-avid lymphomas, modification of the Ann Arbor terminology eliminating A/B qualifiers except for HL, and departure from routine bone marrow biopsy in DLBCL and HL based on functional imaging. FDG-PET utilizing the Deauville 5-point scale was integrated into response assessment.
TABLE 105-3REVISED STAGING SYSTEM FOR PRIMARY NODAL LYMPHOMAS ||Download (.pdf) TABLE 105-3 REVISED STAGING SYSTEM FOR PRIMARY NODAL LYMPHOMAS
| ||STAGE ||SITES ||EXTRANODAL (E) STATUS |
|Limited stage ||I ||One node or a group of adjacent nodes ||Single extranodal lesions without nodal involvement |
| ||IIa ||Two or more nodal groups on the same side of the diaphragm ||Stage I or II by nodal extent with limited contiguous extranodal involvement |
|Advanced stage ||III ||Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement ||Not applicable |
| ||IV ||Additional noncontiguous extralymphatic involvement ||Not applicable |
Bone Marrow Biopsy—Relevance to Staging, DLBCL/Hodgkin Versus Indolent NHL
Bone marrow aspirate and biopsy has historically been recommended as part of staging for both NHL and HL. Bone marrow involvement occurs in 30% to 50% of patients with NHL and is more frequent with indolent histologies. The Lugano revision of the staging criteria has suggested that bone marrow biopsy may not be necessary in DLBCL or HL if functional imaging fails to identify osseous lesions. One must acknowledge, however, that bone marrow involvement with indolent lymphoma is generally not evident on FDG-PET. A bone marrow biopsy should be performed if this knowledge alters clinical management (eg, identification of transformed biology).
Clinical Risk Prognostic Models
Impact of age across all prognostic models
The lymphoma literature is replete with clinical risk models designed to prognosticate outcome in each of the lymphoma subtypes. The most frequently utilized model is the international prognostic index (IPI) that identifies five clinical factors as prognostic variables for PFS and OS in DLBCL both before and after the widespread use of rituximab (Table 105-4). Importantly, chronologic age remains an integral part of many lymphoma clinical risk predictors, including the IPI, the follicular lymphoma IPI (FLIPI), the mantle cell IPI (MIPI), and the HL international prognostic score (IPS). Although an age cutoff of 60 is often used to dichotomously segregate patients into younger and older, it is well appreciated that age is a continuous variable and that a more clinically relevant cutoff above which patients are likely to require treatment modifications exists between 70 and 75 years in the current era. A recently reported modification of the IPI in DLBCL patients specifically older than 60 suggested that age over 70 years conferred additional negative prognostic impact.
TABLE 105-4VARIOUS PROGNOSTIC SCORES ||Download (.pdf) TABLE 105-4 VARIOUS PROGNOSTIC SCORES
|PROGNOSTIC FACTOR |
|IPI ||FLIPI ||FLIPI2 ||MIPI ||PIT ||IPS |
|Age > 60 ||Age > 60 ||Age > 60 ||Age ||Age > 60 or (≤ 60) ||Age > 45 |
|Stage III/IV ||Stage III/IV ||BM involvement ||Ki67 ||BM involvement ||Stage IV |
|PS > 1 ||Hgb < 12 g/L ||Hgb < 12 g/L ||PS ||PS ||Hgb < 10.5 g/L |
|LDH > ULN ||LDH > ULN ||B2M > ULN ||LDH compared ULN ||LDH > ULN ||Albumin < 4 g/dL |
|ENS > 2 ||> 4 nodal sites ||LN diameter > 6 cm ||WBC || || |
WBC > 15
ALC < 600 or < 8% of total WBC count
| || || || || ||Male gender |
|Low (0–1) 2 y OS 84%, 5 y OS 73% ||Low (0–1) 5 y OS 91%, 10 y OS 71% ||Low (0) 3 y PFS 91%, 5 y PFS 80% ||Low 5 y OS 81% ||Low (0) 5 y OS 62.3%, 10 y OS 54.9% ||0 factors 5 y FFP 84%, 5 y OS 89% |
|Low-Int (2) 2 y OS 66%, 5 y OS 51% ||Int (1–2) 5 y OS 78%, 10 y OS 51% ||Int (1–2) 3 y PFS 69%, 5 y PFS 51% ||Int 5 y OS 63% ||Low–Int (1) 5 y OS 52.9%, 10 y OS 38.8% ||1 factor 5 y FFP 77%, 5 y OS 90% |
|High-Int (3) 2 y OS 54%, 5 y OS 43% ||High ≥ 3, 5 y OS 53%, 10 y OS 36% ||High (3–5), 3 y PFS 51%, 5 y PFS 19% ||High 5 y OS 35% ||High-Int (2) 5 y OS 32.9%, 10 y OS 18% ||2 factors 5 y FFP 67%, 5 y OS 81% |
|High (4–5) 2 y OS 34%, 5 y OS 26% || || || ||High (≥ 3) 5 y OS 18.3%, 10 y OS 12.6% ||3 factors 5 y FFP 60%, 5 y OS 78% |
| || || || || ||4 factors 5 y FFP 51%, 5 y OS 61% |
| || || || || ||≥ 5 factors 5 y FFP 42%, 5 y OS 56% |
From a clinical decision-making standpoint, distinctions in older population between “the young old” (65–74 years), “older old” (75–84 years), and “oldest old” (> 85 years) are somewhat arbitrary but have clinical utility in minimizing heterogeneity when devising treatment guidelines. Ultimately however, the variable nature of the aging process mandates that we think beyond chronologic age.
In addition to clinical risk predictors, biologic factors that are either prognostic or predictive, or both, are increasingly sought. In the modern era, with targeted therapies an increased reality, biomarkers to guide therapeutic decision making will be essential. The proliferative index, a measure of cellular division, as assessed by Ki67 percentage, has been demonstrated to have prognostic impact in DLBCL, MCL, and in predicting increased risk of indolent NHL transformation. As genetic and mutational profiling has become more approachable, the cell of origin signature in DLBCL and host immune signatures in FCL and DLBCL have been prognostic, as well as a proliferative signature in MCL.
In DLBCL, the putative cell of origin as identified on GEP is prognostic, with germinal center-derived DLBCL enjoying a better outcome than non-GC (ABC phenotype) with CHOP and RCHOP therapy. IHC models designed to approximate GEP exist (eg, the Hans model based on CD10, BCL6, and MUM1) and are implemented given their clinical utility and availability, but problems exist with sensitivity and specificity. Ultimately, newer molecular techniques will likely supplant IHC in this determination. Additionally, the concurrent presence of the antiapoptotic t(14;18) BCL2 translocation and a cMYC t(8;14) cellular proliferation signal (or less frequently BCL6 translocations) has been termed a “double hit” biology (DH), borrowing a term from breast cancer. Roughly 10% of patients with DLBCL will have DH biology, a finding associated with very aggressive disease, older age, higher CNS risk, and no current standard of care recommendation. A larger population (~1/3) of DLBCL patients may have protein overexpression of BCL and MYC, termed double expressers, and have increased disease risk as well, but to a more variable degree.
Central nervous system evaluation with lumbar puncture and analysis of cerebrospinal fluid (CSF) is important in patients with a clinical suspicion of nervous system involvement or those at high risk for CNS involvement at presentation. CSF investigation should include cell count, glucose, protein, cytology, as well as the more sensitive flow cytometry. This is generally a consideration in aggressive lymphomas and high-grade disease, with involvement rare in mantle cell or indolent lymphomas. Increased risk of CNS involvement historically has been associated with higher clinical risk factors, anatomic sites of involvement such as the testes, breast, multiple extranodal sites, and bone marrow.
Recently, a predictive model for DLBCL risk of CNS relapse was reported. This validated model is comprised of six factors (age, PS, LDH, stage, ENS, and kidney/adrenal involvement) with stratification of CNS relapse based on number of risk factors: low (0–1, 0.8% risk), intermediate (2–3, 3.9% risk), and high (4–6, 12% risk). Although the optimal method (intrathecal or high-dose methotrexate) and the actual magnitude of risk reduction in CNS prophylaxis remain debated, this predictive model is useful when considering the pros and cons in older adults.
Differences in Lymphoma Biology Between Older and Younger Patients
Regarding lymphoma biology, it is clear that in addition to host related factors accompanying the aging process, there are biologic differences in the underlying disease. Inflammatory levels, such as interleukin 6 (IL-6), are higher in older patients with lymphoma and correlate with the presence of B symptoms, increased LDH, advanced-stage, bulky disease, poor performance status, and are associated with poorer failure free and overall survival independent of traditional risk factors. Advancing age has been associated with increasing mutational and genetic heterogeneity and complexity which impact on outcome. GEP studies have confirmed older DLBCL patients more frequently are associated with a prognostically less favorable activated B-cell phenotype (ABC), associated with increased activation of the NF-KB pathway and inferior outcomes with RCHOP therapy. The EBV also has been connected to the inferior outcomes in both older adult DLBCL and HL patients. EBV-positive DLBCL of older adults is a clinical pathologic entity newly recognized by the WHO in the 2008 classification system. These patients are associated with more advanced disease, involvement of multiple extranodal sites, high-risk score, and inferior progression-free survival (PFS) and overall survival (OS).
TREATMENT OF OLDER PATIENTS WITH NON-HODGKIN LYMPHOMA
For the older patient, establishing clinical and disease-associated risk predictors is an essential part of the assessment, but this evaluation still represents an incomplete clinical picture of the individual for the treating oncologist. With increasing age, the physician is often confronted with significant host-related geriatric risk factors that may be equally or more profound than the aforementioned factors and ultimately define the palette of therapeutic options. The oncogeriatric factors of life expectancy, comorbidity, frailty, and geriatric syndromes independently predict treatment-associated morbidity and mortality, and consequently become essential considerations when deriving a treatment strategy. Ultimately, these clinical concerns are most weighty when there is an aggressive histology that is potentially curable, but therapy is associated with very real risks.
As a first step, age-related life expectancy assessment and comprehensive geriatric assessment are valuable tools in making therapeutic determinations. It is instructive to realize that an 80-year-old in average health has a predicted life expectancy of approximately 5 years absent a lymphoma diagnosis. As a result, even in advanced age, aggressive NHL will most frequently be the greatest risk to the patient in all but the most infirmed patients (eg, life expectancy < 1 year). Life expectancy tables are available from the National Comprehensive Cancer Network (NCCN) guidelines. The Lee and Schonberg 4- and 5-year estimates of mortality in older patients are practical web-based tools that can assist in these estimations. Importantly, analysis of the SEER Medicare database suggests approximately 33% of patients with DLBCL age greater than 80 and older received no therapy at all. While at times this may be appropriate, curative and palliative therapy can generally be given to these patients and critical evaluation of factors such as ageism, physician and patient choice, and availability of adequate tools to predict toxicity is needed.
Comorbidity and Frailty Assessments
Although life expectancy evaluation can establish a general backdrop for treatment, the physician is further informed by comorbidity and frailty assessments. Comorbidity is prevalent in older patients, with 60% to 70% of older NHL patients older than 60 years possessing some comorbidity. Frequently used measures include the Charlson comorbidity score and the Cumulative Illness Rating Scale for Geriatrics, both of which capture information distinct from lymphoma-specific prognostic indexes and are independently associated with risk. The presence of comorbidity in NHL and HL patients has been associated with increased treatment-related mortality (TRM), treatment toxicity, lower dose intensity, and higher treatment failure.
Frailty is a distinct syndrome from comorbidity and has its own impact on outcomes. Frailty is often defined practically, with suggested criteria including age greater than 80 or 85, dependence in activities of daily living (ADL), exhaustion, slow gait speed, decreased hand grip, unintentional weight loss, and decreased physical activity. Frail patients have shorter life expectancies than nonfrail patient and have a higher likelihood of toxicity with interventions such as chemotherapy. Thus, frailty identifies a group of patients at greatest risk given lack of functional reserves and palliative chemotherapy approaches are generally recommended in this setting.
Comprehensive Geriatric Assessment
It is recognized that performance status and clinical judgment alone are insufficient when attempting to identify at risk older individuals and may misclassify a significant percent of patients, exposing them to harm or denying curative intent. In this vein, the NCCN, American Society of Clinical Oncology (ASCO), and International Society of Geriatric Oncology (SIOG) guidelines recommend performance of comprehensive geriatric assessment (CGA) in older patients, although the optimal integration of these interventions remains in evolution. A screening assessment (such as the VES-13) or at least ADL/instrumental activities of daily living (IADL) assessment should be performed on all patients. Those with impairments benefit from a more formal CGA analysis. The Cancer and Aging Group (CARG) and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) CGA models are largely self-administered, time efficient, and predictive of serious hematologic and nonhematologic toxicities. Prospective trials integrating these tools into dose-adjustment or treatment choice algorithms are warranted, but in clinical practice, those at highest risk for toxicity should be considered for modifications or reduced-intensity regimens. Instructively, Tucci and colleagues demonstrated that a CGA applied in 173 DLBCL patients older than 69 years segregated fit (46%), unfit (16%), and frail (38%) patients with significantly different outcomes (OS 84% fit vs 47% nonfit, p < .0001) and a lack of clinical benefit from curative intent therapy in the frail category.
The Fondazione Italiana Linfomi (FIL) integrated a CGA tool into a trial treatment paradigm that stratified 334 DLBCL patients older than 65 years as either fit (68%) or frail (29%). Fit patients were randomized on a trial between RCHOP and R-mini-CEOP and had excellent and equivalent outcomes, while frail patients were treated per investigator choice. Frail patients were more frequently older (median age 78, range 65–93), with advanced stage (62%) and high risk (aaIPI 2/3 in 53%), and reported a 5-year estimated OS of 28% despite polychemotherapy administration in three-fourths of patients. TRM was 18% in this group compared with only 8% in the fit group. Prospective trials in the future will need to define therapeutic strategies for both the fit and frail categories based on the CGA to realize the true benefit of these tools.
Pharmacologic Considerations for the Older NHL Adult Patient
It is worth noting that a number of approved agents for the treatment of NHL are associated with peripheral and autonomic neuropathy. In the older individual, although grade 3 neuropathy generally provokes drug modification or cessation, it is important to note that a painful grade 2 neuropathy may inhibit ADL/IADL and increase the risk of falls and impacting quality of life (QOL). Dose reductions and omissions need to be balanced against the potential benefit in a given scenario.
Doxorubicin has proven over the years to be one of the most active and essential agents in the treatment of aggressive histologies such as DLBCL and HL. The anthracyclines are associated with a defined risk of anthracycline-induced cardiomyopathy that is related to cumulative dose (although rarely idiopathic), with risk increasing significantly with doxorubicin equivalents in excess of 400 mg/m2 lifetime. Hypertension is an established risk factor. Infusional doxorubicin and liposomal doxorubicin may have an increased safety margin and a variety of non-anthracycline regimens exist when there is an absolute contraindication that may still preserve a curative intent. The cardioprotective agent Zinecard is not frequently utilized given a lack of data in NHL. It is worth noting a recent Veterans Affairs database analysis that has questioned the benefit of anthracyclines in older patients with DLBCL given associated toxicities.
Special Considerations With Small Molecule Inhibitors in the Older Patient
Ibrutinib is a small molecule inhibitor of Bruton tyrosine kinase (BTK) FDA approved for the treatment of CLL and MCL. Transient increases in lymphocytosis during the first weeks of therapy are likely in on target effects of the drug as lymphoma cell trafficking is modified and cells egressed from lymph nodes into the circulation. With longer follow-up, propensity toward bleeding has been identified with consideration for risk versus benefit in patients requiring antiplatelet her anticoagulation therapies necessary. Concurrent warfarin is generally contraindicated given interactions with CYP3A inhibitors and inducers. New-onset atrial fibrillation has also been reported in less than 5%.
Idelasilib is a small molecule inhibitor of PI3 kinase-δ that is FDA approved for patients with CLL/SLL and refractory FL. This drug has been associated with fatal and/or serious hepatotoxicity, severe diarrhea or colitis that may occur as a later complication, pneumonitis, and intestinal perforation. LFT abnormalities typically resolve with interruption of drug dosing patients can frequently resume therapy. Similar to ibrutinib, transient lymphocytosis is also a class effect with this agent.
DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL both in the United States and globally, representing roughly 30% of all new diagnosis. With a median age at diagnosis of 70 years, DLBCL is in many ways a disease of older individuals, a fact which will be magnified over the next decades as the population sees doubling and tripling of those older than 75 and older than 85 years, respectively. These projections indicate that over the same time, the number of NHL cases will increase by 67%. Hence, there is a pressing need to understand age-related host and disease factors, how they impact therapeutic choices and outcomes, and to develop specific strategies to address these factors.
Based on randomized controlled trials (RCTs), frontline therapy with anthracycline-based chemoimmunotherapy for DLBCL has resulted in overall survival rates of 60% to 70% and represents the best chance for cure, as the majority of relapsed or refractory patients will succumb to the disease. Without therapy, DLBCL is rapidly fatal in a matter of weeks. However, older patients frequently have comorbidities and functional impairment limiting feasibility of standard therapy. Hence, there are significant challenges facing the oncologist who must integrate disease, host, and patient factors with the goal of individualizing treatment decisions for the older DLBCL patient. In this context, oncogeriatric tools are essential to the initial assessment of these patients and augment the lymphoma-specific care plan.
From a practical standpoint, the initial assessment of the older patient with DLBCL is evolving to include parallel pretreatment disease staging, biologic and genetic risk assessment, and oncogeriatric risk assessment to inform decision making. Ideally, these assessments inform the oncologist and patient regarding the disease risk in the context of patient life expectancy, the likelihood of cure or disease control balanced against the likelihood of treatment related morbidity and mortality, and provide recommendations for treatment modification to mitigate these effects.
Biology: Effective Age, Germinal Center Versus Non-GC, and Methodology for Determining Cell of Origin
Chronologic age has factored prominently into the DLBCL landscape, as age is both associated with increased incidence of disease as well as poorer prognosis. Historically, a cutoff of 60 years was utilized in the IPI risk model, as high-dose therapy and stem cell rescue were generally limited above this age category. However, when clinical prognostic models have been revisited in the era of chemoimmunotherapy (eg, RCHOP), this dichotomous cut point has often been revised to 70 to 72 years as a prognostic component. While binary cut points are useful in clinical models, it is recognized that chronologic age is a continuous variable with vast heterogeneity regarding biologic implications for any individual. Consequently, functional definitions of age are preferable and reflect individual physiology.
Biology in older patients
It is readily acknowledged that DLBCL is a heterogeneous disease as evidenced by both varied clinical outcomes and increased understanding of the spectrum of underlying biology. Based on the WHO classification (WHO 2008), the majority of diagnoses in older patients will be classified as DLBCL, not otherwise specified (NOS); potentially adverse disease subsets such as T-cell–rich B-cell lymphoma, immunoblastic morphology, and EBV-associated DLBCL occur in greater frequency in older adults. Although associated with worse outcomes, specific treatment recommendations are lacking for these entities.
DLBCL expressing both cMyc t(8;14) and BCL2 t(14;18) by FISH are termed “double hit” lymphomas and have been associated with very poor prognosis. Double-hit lymphomas diagnosed by FISH may be present in 2% to 11% of new diagnoses. IHC can also identify DLBCL with dual expression of MYC and BCL2, coined double expressing DLBCL, which is also associated with inferior outcomes and may be present in one-third of patients. Optimal treatment is still undefined and increased treatment intensity is not a plausible strategy for most older patients.
Over the last decade, significant advances in molecular genetics have deepened our understanding of DLBCL biology. GEP of DLBCL, NOS has identified at least 2 distinct molecular subsets, namely a germinal center B-cell (GC) and an activated B-cell (ABC) phenotype, both reflecting the putative cell of origin biology. The ABC phenotype, with increased nuclear factor-κB (NF-κB) and chronic BCR receptor activation, is associated with worse outcomes under current standard of care therapy. Furthermore, both genetic complexity and the ABC phenotype increases with increasing age and account in part for worse outcomes independent of clinical predictors. The reality of DLBCL molecular changes, however, extends beyond merely assessing cell of origin, with significant genetic alterations identified in the microenvironment (stromal signals) as well as immune surveillance and antigen presentation aberrations, which are equally important.
In 2015, although increasingly cost-efficient, GEP remained impractical in daily practice and did not, as of yet, define therapy. As a result, surrogate IHC models of COO (eg, Hans, Tilly) have been implemented given ready availability and quick turnaround. Although prognostic value is maintained, the IHC models are fraught with misclassification and poorer reproducibility. Approaches using rapid assessment of predictive biology in paraffin-embedded samples, such as the nanostring predictors Lymph2Cx, are being validated currently and are promising technologies to anticipate in the near future. These discoveries have given us insight into the essential oncogenic pathways involved in the heterogeneity of DLBCL and offer the potential for targeted therapeutic agents.
DLBCL is an aggressive entity with the natural history characterized by rapid progression and death in the absence of treatment. Consequently, chemotherapy is frequently used to extend survival, even among patients were curative intent cannot be achieved. Anthracycline-based chemotherapy has been associated with the greatest cure rates, with CHOP chemotherapy forming the backbone for modern-day therapy. The initial decision regarding the feasibility of anthracycline-based chemotherapy is consequently paramount. This decision must integrate assessments of organ function, clinical judgment, comorbidity, and performance status as previously discussed.
Early-Stage Treatment Paradigms
Therapeutic options for early-stage DLBCL (stage I/II without bulk) are distinct from advanced-stage disease with some overlap. Patients with age as their only risk factor have very good prognosis with combined modality therapy. Treatment approaches were initially defined by the SWOG 8736 which established CHOP × 3 cycles followed by IFRT as superior to CHOP × 8 cycles for PFS and OS at 5 years (PFS 77% vs 64%, OS 82% vs 72%); this difference, however, disappears after 8 years, a fact that should be considered in the context of life expectancy. The addition of rituximab to CHOP × 3 + IFRT was explored in SWOG 0014 in patients with one or more risk factors, with PFS of 88% at 5-year median follow-up. It is worth noting data from the GELA/LYSA group question the benefit of IFRT in older patients following four cycles of CHOP (LNH 93-4), and more recently following four cycles of RCHOP when in CR. Patients with bulky (> 10 cm) disease generally are treated with full course RCHOP ± IFRT for local control.
Whether or not to include radiation consolidation may be informed by disease location, associated RT toxicity, comorbidity, and life expectancy. Radiation should be considered for definitive therapy in patients who cannot tolerate chemotherapy.
Advanced-Stage Treatment Paradigms
The standard of care for initial treatment of DLBCL in both older and younger patients is chemoimmunotherapy comprised of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP 21) given every 21 days for six to eight cycles. The standard of care is based on the LNH 98–5 study, which included patients age 60–80 (median age of 69); 55% of patients were 70 years or older. This study has mature data, with 5-year progression-free and overall survival significantly longer for the rituximab-containing arms (54% and 58% RCHOP compared to 30% and 45% CHOP, respectively). Dedicated RCTs designed to improve upon RCHOP21 have explored upfront consolidative transplantation, dose-dense q14 day regimens, and maintenance rituximab without improvement in survival.
Ongoing efforts are exploring alternative regimens such as the dose-adjusted R-EPOCH regimen and cell-of-origin–directed trials. The DA-R-EPOCH regimen is an infusional chemotherapy regimen that may have improved efficacy in DLBCL, particularly in GC biology, and high proliferative rate tumors (eg, Myc +, high Ki67), and is potentially less cardiotoxic owing to infusional doxorubicin. Phase II data from the CALGB was associated with 5-year TTP and OS of 81% and 84% in all patients. A CALGB RCT comparing RCHOP21 versus DA-R-EPOCH was completed but not reported as of 2015. This regimen can be safely considered in older patients and may have an advantage in higher-risk scenarios (eg, double-hit biology). Cell-of-origin directed approaches are being explored in clinical trials and have taken into consideration differential activity of certain agents in the nongerminal center (ABC) phenotype. Agents such as bortezomib, ibrutinib, and lenalidomide all have phase I and II data supporting combination with RCHOP, with phase III studies ongoing globally.
Radiation consolidation to sites of bulk or residual masses may be beneficial in selected cases. IFRT has been associated with increased local control and PFS, but not OS. However, in older patients with competing nonlymphoma comorbidities for life expectancy and a lack of effective second-line options, this initial improvement in disease control may be worthwhile. Careful discussion of these pros and cons is often needed.
Patients who relapse following RCHOP chemotherapy have a poor prognosis, even when second-line therapy and subsequent high-dose therapy and autologous stem cell rescue can be utilized. For the vast majority of older individuals, this intensive strategy is not feasible due to age-related comorbidity and increased TRM associated with transplant approaches. In this setting, goals of care shift to disease control and palliation.
Prephase concept and reduced intensity
Often at initial presentation, disease-related factors impair host performance status and are associated with treatment-associated morbidity and mortality. The German NHL high-grade study group has utilized a concept termed “prephase” to mitigate the impact of decreased functional status initially. Employing a week of corticosteroid and a single dose of vincristine before the initiation of therapy, the RICOVER60 study suggested there was a 50% reduction in cycle 1 and 2 TRM as a consequence of this maneuver. While dedicated validation of this approach is needed, other prospective studies have suggested there is clinical benefit to such a concept; clinicians frequently employ steroids to improve functional status in anticipation of starting definitive chemotherapy.
Reduced or nonanthracycline-based curative intent
In clinical scenarios where RCHOP is not deemed feasible, there exist a variety of dose-reduced regimens, with relative dose intensities of 50% to 70% standard dosing, and a number nonanthracycline regimens that maintain curative potential. In general, the trade-off includes a reduction in efficacy with the advantage of reduced toxicity and TRM. Direct comparative data are frequently lacking in this area, with data more frequently culled from retrospective cohorts or phase II trials (Table 105-5).
TABLE 105-5REDUCED DOSE OR NONANTHRACYCLINE THERAPY ||Download (.pdf) TABLE 105-5 REDUCED DOSE OR NONANTHRACYCLINE THERAPY
|REGIMEN ||N ||PLANNED RDI ||AGE MEDIAN (RANGE) ||ORR (CR/PR) ||EFS ||OS ||TRM |
|RCHOP21 (Phase III) ||N = 202 ||100% ||69 y (60–80) ||83% (75%/7%) ||57% @ 2 y ||70% @ 2 y ||6% |
|RCHOP21 (retrospective) ||N = 61 ||70% ||76 y ||87% (79%/8%) ||57% @ 2 y ||68% @ 3 y ||NR |
|R-mini-CHOP (Phase II) ||N = 149 ||~50% ||83 y (80–95) ||74% (63%/11%) ||47% @ 2 y (PFS) ||59% @ 2 y ||8% |
|DRCOP (Phase II) ||N = 80 ||NA ||69 y (61–92) ||86% (75%/11%) ||60% @ 3 y ||74% @ 3 y ||5% |
|Nonanthracycline regimens |
|R-miniCEOP (Phase III) ||N = 114 ||100% ||73 y (64–84) ||81% (68%/13%) ||54% @ 2 y ||~74%@ 2 y ||6% |
|R-GCVP (EF ≤ 55%) (Phase II) ||N = 61 ||NA ||76 y (52–90) ||61% (39%/23%) ||50% @ 2 y (PFS) ||56% @ 2 y ||NR |
|R-Bendamustine (Phase II) ||N = 14 ||NA ||85 y (80–95) ||69% (54%/15%) ||40% @ 2 y (PFS) ||40% @ 2 y ||0% |
|CR, complete response; EFS, event free survival; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression free survival; PR, partial response; RDI, reduced dose intensity; TRM, treatment related mortality. |
DLBCL patients characterized as very old adults, for example, over the age of 80 years, or with associated geriatric syndrome and/or frailty are under represented in clinical trials with a lack of evidenced-based guidelines. Typically, full-dose chemotherapy is not approachable, but often curative regimens can still be considered with modifications designed to mitigate serious toxicity. A phase II GELA study specifically in patients older than 80 years (n = 149) investigated a reduced intensity R-mini-CHOP protocol with 2-year PFS and OS of 47% and 59%, respectively, and maintained at 4 years. A variety of other nonanthracycline options also exist, such as CEPP, CDOP, CNOP, CEOP, and GCVP, all given with rituximab.
Response Assessment and Follow-Up
Interim restaging is performed to identify scenarios where disease is not responding or progressing despite therapy. This confirmation is particularly important in older adults where toxicity may be significant. Interim PET scans have been demonstrated to retain excellent negative predictive value, but questionable positive predictive value that has not allowed changes in therapy; consequently, interim PET scans are not recommended outside clinical trials. PET scans at the end of therapy, however, are now standard and remain very predictive of outcome.
Surveillance imaging as a routine post therapy has been called into question, with a lack of evidence supporting improved outcomes with screening CT scans and concern over false positives and exposure to medical radiation. For advanced-stage patients, CT scans every 6 months for 2 years are recommended currently, balancing the increased risk of relapse during this time interval with a desire to limit exposure.
High-Dose Therapy and Autologous Stem Cell Rescue in Older Patients
High-dose chemotherapy followed by autologous stem cell rescue (HDT/ASCR) was established in the PARMA study as the recommended second-line approach in chemosensitive transplant-eligible patients. In the absence of HDT/ASCR, relapsed DLBCL therapy is generally not curative. Unfortunately, there are limited data reporting the safety and efficacy of HDT/ASCR in the older patient. The Center for International Blood and Marrow Transplant Research (CIMBTR) has reported a 28% increase in the number of HDT/ASCR procedures in the United States when comparing 1994–1995 to 2004–2005. Commensurate with this increase, the proportion of patients 60 years or older undergoing HDT/ASCR during the same period went from less than 7% to 35%.
Given the significant potential for morbidity and mortality with HDT/ASCR, patient selection in the older patient is paramount. Factors considered include age, comorbidities, functional status, and psychosocial support systems. The second-line aaIPI (PS, LDH, stage) has been confirmed in a number of trials as predictive of PFS and OS with an intent to transplant; 3-year estimated event-free survival (EFS) for low/intermediate-risk versus high-risk patients was 40% versus 18% (p < .001). A Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) also exists and high-risk scores are associated with decreased likelihood of receiving transplant and OS. Despite age-related physiologic changes, in general age is not a limiting factor when considering the ability to mobilize and collect stem cells, although complete count recovery may be slower post transplant in older individuals. TRM in NHL patients older than 55 years in the CIBMTR database was 15% and increased 1.86 times compared to their younger counterparts. This may be as high as 18% to 19% for individuals older than 70 years at transplant.
The largest randomized study of second-line therapy followed by HDT/ASCR (Collaborative Trial in Relapsed Aggressive Lymphoma [CORAL] study) included patients up to age 65, with a median age of 55. In this patient population, the intent to treat (ITT) EFS was 31% for all patients, with identified prognostic factors of relapse less than 12 months from prior therapy, prior rituximab, and the second-line age-adjusted IPI. For patients with early relapse following prior rituximab-based therapy, the ITT EFS was only 23%. Given these modest results in younger patients, one must be selective in recommending HDT/ASCR in the older individual. Early referral to a transplant center for evaluation, cardiac and pulmonary assessment, second-line aaIPI, and CGA should all likely precede initiation of intensive second-line regimens such as R-ICE or R-DHAP when transplant is the goal.
BURKITT LYMPHOMA AND HIGH-GRADE DLBCL WITH FEATURES INTERMEDIATE BETWEEN BL/DLBCL
Burkitt lymphoma (BL) is the prototypic high-grade lymphoma, and the history and treatment approaches of this disease have established many principles of lymphoma therapy. For instance, BL was the first malignancy associated with a virus (EBV), BL led to the identification of the tumor lysis syndrome, and treatment evolution defined intrathecal and CNS lymphoma therapy. BL has a propensity for CNS involvement. Endemic BL in Africa is associated with an interplay between EBV and malaria, prototypically presenting as a rapidly enlarging jaw mass in pediatric and adolescent patients. In the United States, BL more frequently is sporadic (or HIV associated) and less frequently associated with EBV (30%). Intra-abdominal presentation may dominate, with extranodal sites of involvement typical (CNS up to 40%, BM up to 70%).
The 2008 WHO classification recognizes it may not always be possible to distinguish between a high-grade DLBCL and BL, with treatment recommendations favoring the high-grade paradigms when feasible. The typical pathologic findings include a “starry sky” appearance caused by a monotonous population of medium- to large-size B lymphocytes with a near 100% proliferative rate and foamy macrophages engulfing apoptotic bodies. Flow and IHC typically reflect sIg(+), CD10(+), CD20(+), TdT(–), Ki67 ≥ 95%, BCL2(–), BCL6(+), and MYC [t(8;14) in 80% or t(8;22), t(2;8)] as a sole rearrangement. GEP may help distinguish between DLBCL with MYC and BL, but this is not common in clinical practice.
Treatment in the Older Adult With BL and Related High-Grade BL/DLBCL
Historically, standard of care regimens for BL require intensive therapy with non–cross-resistant agents that cross the blood-brain barrier. Initial therapy is generally rendered in the hospital, with tumor lysis prophylaxis mandatory. CHOP therapy has been insufficient to achieve cure. With current approaches evaluated in the SEER database (2002–2008), 5-year OS estimates are 56%. Roughly one-third of patients will be older than 60 years at diagnosis in the United States. The survival of older adults is less favorable compared with younger counterparts. Regimens associated with the best outcomes include CODOX-M-IVAC, hyperCVAD, and DA-R-EPOCH. Modifications of the CODOX-M-IVAC regimen have been published that decrease the associated toxicity and integrate rituximab; these modification may be more approachable in older patients. The hyperCVAD regimen is associated with increased toxicity in patients older than 65 years and often is not feasible. DA-R-EPOCH may be safest from a toxicity standpoint, and validation of this regimen in BL is under way. Cases of double-hit DLBCL and B-cell lymphoma, unclassifiable with features intermediate between DLBCL and BL, are often treated with BL regimens, acknowledging robust data are lacking and optimal management has yet to be defined.
Mantle cell lymphoma (MCL) is a rarer subtype of NHL with roughly 7000 new cases annually in the United States. Historically, this entity was associated with median OS of only 2 to 3 years and paradoxically shares the incurable features of indolent lymphoma with the behavior of an aggressive disease biology. In the modern era, MCL has been associated with significant advances in biologic understanding, therapeutic options, and increased median survivals of 5 to 7+ years. The median age of MCL patients at diagnosis is 65 years, with a male predominance and a propensity for bone marrow and GI involvement. Advanced-stage disease is the norm, with localized stage I and II disease rarely present. Asymptomatic patients may be identified incidentally by screening colonoscopy, with a lymphomatoid polyposis presentation characterized by innumerable colonic polyps. It is now appreciated that more indolent presentations of MCL also exist, often with BM or GI only presentations. Although not sufficient for the development of MCL alone, dysregulation of cell cyclin D1 (rarely D2 or D3) due to translocation 11;14 is a hallmark of MCL.
MCL can generally be distinguished from similar morphologic appearing entities (eg, CLL/SLL, MZL, LPL) with IHC/flow and FISH. The typical immunophenotype consists of CD5(+), CD10(–), CD20(+), CD23(–/+), CD43(+), and cyclin D1(+) associated with a translocation of chromosomes 11 and 14. Nuclear overexpression of SOX11 is present frequently and is associated with prognosis. A blastic MCL variant, characterized by p53 derangement, myc, high proliferative rate, and a more aggressive disease course, is also recognized and poses a therapeutic challenge.
Upfront Transplant Versus Nontransplant Approaches
MCL remains an incurable entity with standard therapeutic approaches today. For the rare patients with limited-stage disease (I, II), a combined-modality approach with RCHOP and IFRT is favored based on retrospective data. In 2015, a dichotomy existed between upfront HDT/ASCR approaches and nontransplant approaches. HDT/ASCR is associated with increased PFS in randomized data but does not cure the disease, and consequently, a discussion of QOL and morbidity versus disease control is central to this discussion. In patients deemed eligible for HDT/ASCR, the cumulative data suggest that cytarabine-containing induction regimens such as hyperCVAD or the European MCL Network RCHOP/RDHAP regimen; randomized data comparing RCHOP/RDHAP versus RCHOP with HDT/ASCR consolidation (age ≤ 65 years) showed an improved TTF for the cytarabine-containing arm (88 vs 46 months, p = .038), with a survival advantage noted as well (not reached vs 82 months, p = .045). The hyperCVAD and upfront transplant approaches, however, are associated with increased toxicity in older patients and may not be feasible for the majority of MCL patients given median age at presentation. Consequently, for the older patient, nontransplant approaches are generally recommended.
Anthracycline-Based Induction RCHOP, VR-CAP, Versus BR
The majority of older patients presenting with MCL will best be served with a nontransplant approach. In early studies, the addition of rituximab to CHOP improved response rates, but unlike other NHL scenarios it did not translate into increased survival. Two randomized studies have defined anthracycline-based initial therapy, with a European MCL network phase III study dedicated to patients older than 60 and ineligible for HDT/ASCR randomizing patients first to RCHOP versus R-FC and secondarily to maintenance rituximab or interferon-α. This study established RCHOP induction followed by maintenance rituximab as superior to R-FC or interferon. OS was improved with maintenance in RCHOP-treated patients. Four-year OS rate for patients treated on this arm was 87%, with a median duration of response of 6+ years.
A second randomized phase III study evaluated the proteosome inhibitor bortezomib (FDA approved for relapsed/refractory MCL) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP, n = 243) versus RCHOP (n = 244); the median age of patients was 66 (range 26–88) with advanced stage in 95%. At 40-month follow-up, median PFS was double (24.7 vs 14.4 months) for VR-CAP without a survival advantage realized. Toxicity was comparable, although slightly higher for VR-CAP.
Taken together, the standard of care for older patients with MCL is chemoimmunotherapy with maintenance rituximab consolidation consideration (data are following RCHOP).
Other approaches have included initial treatment with rituximab and bendamustine based on the StiL (Study Group Indolent lymphomas) phase II trial subgroup with MCL and supportive data from the US BRIGHT study. Overall response rates with this regimen are similar to RCHOP with longer PFS and less toxicity, although there was no impact on OS. This regimen may be preferable when comorbidity limits anthracycline approaches. The purine analogue cladribine has been evaluated in phase II studies with good outcomes in older patients as well.
Second-line therapy remains challenging, although increasing understanding of biology and recently approved agents such as bortezomib (targeting the proteasome), ibrutinib (targeting BTK), and the immunomodulatory agent lenalidomide have increased therapeutic strategies beyond cytotoxic chemotherapy. Integration of these agents into initial treatment is the focus of current research.
FOLLICULAR LYMPHOMA/INDOLENT LYMPHOMAS
Follicular lymphoma (FL) is the second most common NHL histology in the United States, accounting for roughly 30% of new cases. Prevalence of this disease is much greater than incidence, owing to a natural history with median survivals improving to greater than 15 years. FLs are the prototypical indolent or slow-growing lymphoma, characterized by systemic disease with a protracted disease course associated with waxing and waning adenopathy that is frequently asymptomatic and may not require therapy.
At presentation, the majority of patients with follicular lymphoma will have painless adenopathy, with B symptoms noted in less than 25% of patients, and systemic disease present with morphologic involvement of the bone marrow in up to 70%. Female gender is slightly more common than male gender. Median age is in the sixth decade. Although therapeutic advances have increased median survival, FCL remains a chronic illness that is characterized by the need for intermittent therapy with generally shorter and shorter response intervals. Marked heterogeneity does exist in disease course, with perhaps 10% to 15% of patients experiencing a more aggressive disease course with shorter survival, while many will have intermittent impact on their daily life.
FL is characterized morphologically by increased number and heterogeneity of lymphoid follicles with disruption of the normal nodal architecture and ablation of interfollicular space. As a result of this fairly consistent morphologic presentation, there is very high concordance between pathologists (> 90%) regarding an FCL diagnosis based on histology alone. A grading system (grades 1–3) based on increasing number of centroblasts per high-power field (hpf) is employed, with grade 3 divided into 3A and 3B subtypes. Concordance with this grading system is less reliable than the initial diagnosis, with distinction between grade 1 (< 5 centroblasts/hpf) and grade 2 (6–16 centroblasts/hpf) clinically insignificant. Grade 3 FCL may benefit from anthracycline-based therapy and DLBCL paradigms are often followed. Nuanced data suggest 3A may behave more indolently and that FCL 3B truly has a different biology and more aggressive behavior, although these distinctions remain challenging.
Immunophenotyping with IHC or flow cytometry is essential to establishing the diagnosis, with a characteristic pattern consisting of CD20(+), CD10(+), BCL2(+), CD23(±), CD43(–), CCND1(–), and BCL6(+). Rare cases may be CD10 or BCL2 negative. Ki67 immunostaining is helpful as higher proliferative rates are associated with more aggressive clinical behavior or overt transformation. GEP has identified the microenvironment milieu and attendant host immune response as a potentially important determinants of prognosis.
Genetically, over 90% of cases have a translocation involving the immunoglobulin heavy chain promoter on chromosome 14 and the antiapoptotic BCL2 gene of chromosome 18 (t[14;18][q32:q21]). Although a hallmark of FCL, the t(14;18) translocation alone is not sufficient for the development of FCL and is not prognostic; in fact, a proportion of the general population will harbor this translocation in their peripheral blood and may never develop disease. This is perhaps not a surprise, given the dynamic nature of the normal germinal center B cell selection process as B lymphocytes undergo clonal expansion, somatic hypermutation, and class switch recombination by design. This inherent and necessary mutability increases the likelihood of genetic and epigenetic events involved in lymphomagenesis.
Many patients will present with advanced-stage disease but will not require immediate intervention. Asymptomatic patients with low burden of disease may be expectantly monitored with no detrimental effect on overall survival. This is supported by randomized studies over the last decades that have explored expectant monitoring at diagnosis versus both chemotherapy (chlorambucil) and immunotherapy alone (rituximab). In each instance, the early initiation of therapy did not improve long-term disease-specific or overall survival, supporting an expectant monitoring approach. Importantly, in the original UK study, up to 40% of patients older than 70 years never required treatment for their FCL. The median time to treatment in controlled settings has generally been about 3 years. Fascinatingly, spontaneous regression of adenopathy in FCL is well established and may occur in 10% to 15% of patients, further supporting a contention that expectant monitoring in the absence of criteria for therapy is valid. Efforts to harness the presumed immune-mediated improvements in disease (eg, vaccine and checkpoint blockade approaches) have been a continual area of investigation with proof of concept demonstrated, but there is no widely validated approach.
Currently accepted indications for therapy, generally chemoimmunotherapy in the modern era, are derived from clinical trial criteria established by the French in the context of clinical trials (termed the GELF criteria) and adopted by the NCCN guidelines. These criteria generally relate to tumor burden (Table 105-6).
TABLE 105-6INDICATIONS FOR THERAPY IN FOLLICULAR LYMPHOMA ||Download (.pdf) TABLE 105-6 INDICATIONS FOR THERAPY IN FOLLICULAR LYMPHOMA
|HIGH TUMOR BURDEN INDICATIONS FOR THERAPY: FCL |
|At least one of the following: |
|3 distinct nodal sites, each ≥ 3 cm |
|Single nodal site ≥ 7 cm |
|Symptomatic splenomegaly |
|Cytopenias (WBC < 1 and/or PLT < 100 × 109/L) |
|Leukemic disease (circulating cells > 5 × 109/L) |
|Pleural effusions, peritoneal ascites |
|B symptoms |
|LDH elevated or B2M ≥ 3 g/dL |
|PS ≥ 1 |
Although the majority of patients will present with advanced-stage disease, roughly 5% to 10% will be diagnosed with localized disease. Patients with localized disease (stage I or II) may be treated with curative involved site radiotherapy (ISRT) of 24 to 30 Gy. In these instances, it is essential that complete staging with imaging (CT neck, CAP, ± PET) and bone marrow biopsy be accomplished to ensure there is no occult disease. When employed for localized disease, IFRT may result in roughly 50% of patients remaining long-term disease free. Patients with stage I disease and small volume (< 3 cm) may derive the greatest benefit. Despite this fact, practice patterns in the United States from the National Lymphocare study suggest a minority of early-stage FCL patients actually received RT; expectant monitoring is reasonable in some patients. Combined modality approaches may improve PFS but have not demonstrated increases in OS. Patients with bulky FCL are generally managed according to advanced-stage strategies.
Therapy for advanced-stage FCL is generally indicated when there are criteria indicating increased tumor burden and symptomatic disease. Current therapies are not curative, and consequently the goal is resolution of disease symptoms and maintenance of remission, with attention to toxicity. FL and lymphomas, in general, are very responsive to immunotherapy alone and in combination with chemotherapy, as well as radiation, with a rapid expansion of available agents in the current era. Current first-line strategies follow a number of broad themes based on outcomes for RCTs. In almost all instances, the addition of rituximab to a chemotherapy backbone has consistently resulted in improved response rates and increased PFS, as well as of evidence of increased OS. Alkylator-based regimens (eg, RCHOP and R-CVP), purine analogue regimens (eg, R-FCM), and rituximab-bendamustine have all been evaluated in the frontline treatment of symptomatic FCL. Overall response rates are generally in the 80% to 95% range, with expected median response durations over 2 years. The PRIMA study demonstrated a PFS benefit from maintenance rituximab (rituximab 375 mg/m2 every 2 months for 2 years) compared with observation following chemoimmunotherapy induction, with a benefit maintained on long-term follow-up. Based on the FIT study, consolidative RIT is a consideration following chemotherapy induction.
Bendamustine is an alkylating agent with a purine-like benzimidazole ring component that is not cross-resistant with other alkylating agents. This agent has demonstrated significant activity (alone and with rituximab) with a favorable toxicity profile. Two randomized studies (StiL and BRIGHT) have compared RCHOP induction to R-bendamustine (BR) in indolent lymphoma, with demonstration of similar ORR (increased CR) and longer PFS with BR, with less frequent grade 3/4 toxicity (alopecia, neutropenia, infection) with BR.
In selected instances, such as older frail patients in whom systemic therapy will be poorly tolerated, low-dose ISRT (4 Gy) may be effective palliation. Single-agent rituximab monotherapy has proven activity in the initial and relapsed settings. Rituximab remains an initial option in frailer patients or those with low-risk profiles, with PFS of roughly 18 months in the upfront setting.
The choice of initial regimen
The choice of initial regimen is based largely on the synthesis of both disease and host factors, integrating comorbidity concerns, side-effect profiles, and life expectancy considerations. Chemoimmunotherapy, incorporating rituximab with a chemotherapy approach, is the accepted standard of care, but which chemotherapy regimen to choose has not been determined by randomized trials. Studies from the Italian Lymphoma Group have suggested that long-term outcomes with alkylator-based therapy initially may be superior to purine analogues in terms of sequence, likely owing to long-term side effects of purine analogues. The favorable toxicity profile of rituximab-bendamustine has led to this being a very attractive initial approach. Biologic-based inductions, such a rituximab plus the immunomodulatory agent lenalidomide, are currently being compared to chemoimmunotherapy (RCHOP or R-bendamustine) in randomized trials.
At relapse, the selection of salvage regimens depends on the efficacy and tolerability of prior therapies. Rituximab is generally included if the benefit from initial therapy was more than 6 months, and data support maintenance rituximab in the relapsed setting as well. Non-cross-resistant regimens are preferable generally. Radioimmunotherapy with 90Y-ibritumumab tiuxetan and 131I-tositumumab represents an effective approach and is a particular consideration in older patients with comorbidities not appropriate for chemotherapy. The oral phosphatidylinositol 3-kinase (PI3K) inhibitor idelesalib has proven safety and efficacy in relapsed indolent NHL refractory to rituximab and alkylators. HDT/ASCR is a consideration in select patients with short remission duration (< 2 years) from initial chemoimmunotherapy induction and physiology that allows this consideration.
Allogeneic stem cell transplantation is potentially curative in low-grade lymphomas; generally only a consideration in younger patients, the approachability of allogeneic stem cell transplant in older patients is increasing and may be considered in very select cases.
Over the disease course of FCL, up to 40% to 50% of patients may experience transformation to a more aggressive biology that is overwhelmingly DLBCL in appearance. Clinically, transformation is often heralded by a rapidly growing nodal mass, new-onset B symptoms, hypercalcemia, elevated LDH, increased Ki 67%, and higher standardized uptake values (SUVs) on FDG-PET. The rate of transformation is roughly 1% to 3% per year, with a potential plateau of this risk around 12 to 15 years based on longitudinal retrospective studies. Patients with high FLIPI scores and grade 3 biology may be at increased risk of transformation, but to date, there is no convincing evidence that the risk of transformation is modified by either watchful waiting as an initial approach or earlier institution of anthracycline-based therapy. Genetic events associated with transformation include the accumulation of BCL6, p53, and cMyc abnormalities, with the FISH double-hit entity (t[14;18] and t[8;14]) often arising in this context.
Once transformation is documented, treatment generally follows DLBCL paradigms, with the goal of therapy to eradicate the aggressive life-threatening clone. Median survival following transformation is reported at less than 2 years, but patients with de novo transformed DLBCL and limited extent of transformation may have better outcomes. Some groups advocate for consolidative HDT/ASCR in first CR, but this is less often a consideration in older individuals. Of note, the vast majority of patients with FL who die have DLBCL as the cause of death.
MARGINAL ZONE LYMPHOMA: NODAL AND EXTRANODAL MALT LYMPHOMA
Marginal zone and MALT lymphomas represent 8% to 10% of NHL. Marginal zone lymphomas comprise a number of clinical pathologic presentations with nodal, splenic, and extranodal presentations in which the malignant B cell is thought to originate from a B lymphocyte derived from the marginal zone of the lymphoid follicle found in the spleen, lymph nodes, and mucosal lymphoid tissue sites. Typical immunophenotyping demonstrates a CD20(+), CD5(–), CD10(–), CD23(±), cyclin D1(–) pattern. MYD88 may be helpful in excluding Waldenström macroglobulinemia.
Nodal marginal zone lymphomas are similar in their behavior to FL, with generally parallel treatment paradigms applied. Splenic marginal zone lymphoma is characterized by splenomegaly, at times massive, and systemic bone marrow and peripheral blood involvement with splenic villous lymphocytes histologically.
The extranodal marginal zone lymphomas, MALT lymphomas, most commonly present in the stomach (50%), although alternatives extranodal sites include the orbit (7%–12%), intestine, thyroid, lung (8%–14%), skin (9%–12%), breast, salivary glands, urinary bladder, kidney, and, rarely, CNS. These presentations are often localized stage IE or IIE disease; systemic staging is required, however, when local therapy is being considered.
Patients with marginal zone lymphomas generally have good outcomes with prolonged disease courses measured in years. A SEER database analysis suggests 5-year relative survivals of 89% with MALT lymphomas, 80% with splenic marginal zone lymphomas, and 76.5% with nodal marginal zone lymphoma. Expectant monitoring is frequently employed as well as a variety of less intensive therapeutic options including monoclonal antibodies, chemoimmunotherapy, and radiation.
The biology related to MALT lymphoma has defined in many ways an established concept of lymphomagenesis dependent on chronic antigenic stimulation of B-cell population through chronic inflammation in an extranodal site. The most frequently involved organ is the stomach, where there is direct evidence that chronic gastritis induced by the microbial pathogen Helicobacter pylori leads to gastric MALT lymphoma. This antigenic drive model has been implicated in a number of settings, with both infectious (hepatitis C, Borrelia burgdorferi, Chlamydia psittaci) and autoimmune (Sjögren and Hashimoto thyroiditis) antigens associated with a risk of marginal zone lymphomas (Table 105-7). Early on in this antigenic cascade, elimination of the antigenic drive may be sufficient to cause regression of the lymphoma. This is most clearly evident with antibiotic eradication of H pylori and regression of clinically evident gastric MALT lymphoma. Gastric MALT lymphomas that harbor an API2/MALT1 translocation (t[11;18][q21;q21]) may be less likely to respond to antibiotics; in these instances, the MALT lymphoma may be driven by activation of NF-κB, acting as a row survival signaling pathway for malignant B cell.
TABLE 105-7PRESUMPTIVE ANTIGENIC DRIVERS IN MARGINAL ZONE LYMPHOMA ||Download (.pdf) TABLE 105-7 PRESUMPTIVE ANTIGENIC DRIVERS IN MARGINAL ZONE LYMPHOMA
|EXTRANODAL SITE ||PRESUMPTIVE ANTIGENIC-DRIVE ||GENETICS |
|Gastric ||Helicobacter pylori ||t(11;18)(q21;q21) API2/MALT1; t(1;14) BCL10 |
|Intestinal ||Campylobacter jejuni || |
|Orbit ||Chlamydia psittaci ||t(14;18) MALT1/IgH; t(3;14) FOXP1 |
|Parotid ||Sjögren syndrome autoantibodies ||t(14;18) MALT1/IgH |
|Thyroid ||Hashimoto thyroiditis ||t(3;14) FOXP1 |
|Skin ||Borrelia burgdorferi ||t(1;14); t(14;18) MALT1/IgH; t(3;14) FOXP1 |
|Splenic ||Hepatitis C || |
|Lung || ||t(11;18)(q21;q21) API2/MALT1; t(1;14) BCL10 |
Splenic marginal zone lymphoma historically was treated with splenectomy when therapy was indicated with excellent outcomes and treatment-free interval measured in years following surgical resection. There is an association with hepatitis C virus which may be causative in certain instances. With the advent of curative treatment for hepatitis C, treatment of the underlying virus is advised whenever possible and may lead to regression of lymphoma. Rituximab monoclonal antibody monotherapy has arisen as a very effective therapeutic strategy that can be repeated and has supplanted splenectomy as a first-line consideration, particularly in older individuals. More resistant disease has been addressed with purine analogs as well as alkylator-based therapy (CHOP-like). Vaccination against encapsulated organisms should be considered given the potential role for splenectomy.
Gastric MALT lymphomas associated with H pylori infection are initially treated with antibiotics to eradicate the antigenic drive. Regression of the clinically evident lymphoma can occur with high frequency but may involve over months and require repeat EGD surveillance to ensure resolution. Interestingly, molecular evidence of the lymphoma clone may persist without clinically relevant disease in the absence of the antigenic drive. Predictors of a decreased likelihood of response with antibiotics include genetics, thickness of gastric wall involvement, and H pylori status.
Stage IE or IIE Helicobacter-negative gastric MALT lymphomas or antibiotic-resistant disease can be very effectively treated with involved field radiotherapy with estimated 10-year relapse-free rate and overall survival rate of 74% and 89%, respectively. Transformation to DLBCL does occur with gastric MALT lymphomas and generally requires chemoimmunotherapy ± radiation to eradicate. There are a few reports suggesting antibiotics may be considered in this scenario with institution of chemoimmunotherapy should antibiotics fail. Surgical resection is no longer a recommended modality for this entity.
In a similar vein, nongastric MALT lymphomas that are localized (stage IE or IIE) are frequently managed with expectant monitoring, involved site radiotherapy, or single-agent monoclonal antibody therapy. More advanced or disseminated disease is approached in a similar fashion to FL treatment paradigms.
Peripheral (Mature) T-Cell Lymphoma
A detailed description of the peripheral (mature) T-cell lymphomas (PTCLs) is beyond the scope of this chapter. PTCLs are a heterogeneous group of lymphoproliferative disorders derived from postthymic T cells and make up 10% to 15% of all NHL diagnoses, generally with poor prognosis. They can clinically be divided into aggressive histologic subtypes predominated by: peripheral T-cell lymphoma NOS, angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), NK/T cell lymphoma, and anaplastic large cell lymphoma divided into ALK-positive and -negative cases. Adult T-cell lymphoma/leukemia is an aggressive disease associated with HTLV-I infection with prolonged latency of over five decades. HTLV-I is endemic in Japan and in the Caribbean basin and remains a difficult disease to treatment. There is significant global variation in the frequency of T-cell lymphomas. Rare entities exist as well such as enteropathy associated T-cell lymphoma and gamma delta hepatosplenic T-cell lymphoma.
Older individuals have an age-associated increased risk of AILD as well as ALK-negative anaplastic large cell lymphoma when these subtypes are present. AILD usually presents with generalized adenopathy, frequently with associated hepatomegaly or splenomegaly, hypergammaglobulinemia, eosinophilia, rash, and fever. CHOP-based chemotherapy has been insufficient for the vast majority of patients in achieving curative outcome and new therapeutic strategies for T-cell lymphomas are a very active area of clinical investigation. When feasible, upfront transplantation following induction therapy may result in long-term disease-free survival of roughly 40% generally in younger individuals. Recent new agents specifically approved for treatment in T-cell lymphomas include Pralatrexate, Romidepsin, and Belinostat, all with a roughly 30% overall response rate. Brentuximab vedotin is an antibody drug conjugate targeted against the cell surface CD30 antigen with potent activity in anaplastic large cell lymphoma.
Mycosis fungoides is a cutaneous T-cell lymphoma that frequently confront the dermatologist and internist. Preexisting history of eczema-like lesions or psoriasis is often present for several years prior to a definitive diagnosis. Skin lesions progress from a patch to a plaque stage and ultimately to more systemic illness with tumor or Sézary syndrome characterized by erythroderma and circulating tumor cells. Early therapeutic interventions include topical therapy such as glucocorticosteroids, topical mustard, phototherapy including PUVA, retinoids, and electron beam radiotherapy.
Hodgkin lymphoma (HL) is the most common lymphoid neoplasm in young patients, with a median age at diagnosis of 38 years. A bimodal age peak has been long reported and persists despite refinements in diagnostic approaches reclassifying some classic Hodgkin lymphomas (cHL) as T-cell-rich B-cell lymphoma. In population-based analyses, 15% to 35% of patients will present with disease over the age of 60 and pose a particularly difficult dynamic for the treating oncologist. If therapy can be given safely, these patients can be cured, but often, they have significant comorbidity that may limit curative regimens. Older patients are also less represented in clinical trials (< 5% of HL trial demographics are older) leaving less guidance and fewer advancements in the treatment of older patients. In the current era, more than 80% of younger patients will be cured with frontline therapy. Unfortunately there remains a significant gap in curability for older patients due to multiple factors including disease biology, host biology, comorbidity, and less ability to effectively administer curative intent therapy.
Biology and Prognostic Models in Older Patients
HL is an uncommon malignancy characterized pathologically by the presence of malignant multinucleated giant cells, eponymously termed “Reed-Sternberg” cells after the defining pathologists, which have a typical IHC profile with expression of CD15 and CD30, while generally CD20 negative (< 40%), in the setting of an inflammatory microenvironment replete with a background milieu of eosinophils, plasma cells, and histiocytes. Four histologic subtypes are recognized: nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted cHL. Another subtype of HL, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), is even rarer, both in terms of incidence (only 5% of all HL) and presentation at advanced age. NLPHD has a more indolent disease course, is typically CD20(+), while negative for CD15, and rarely expresses CD30.
A number of reports have implicated more aggressive disease biology in older patients with cHL compared with younger patients at presentation, including higher-risk scores, mixed cellularity histology, advanced stage, and EBV association. Staging is described above and includes PET imaging at baseline. In all HL patients, but particularly those who are older at diagnosis, assessment of LV function and pulmonary function testing with DLCO is essential prior to considering anthracycline-based therapy that includes bleomycin.
The definition of “older” in HL has often been at an earlier chronologic age (45 or 50) based on prognostic models, although clinically relevant age-related concerns impact care in those generally over 60 years. The IPS was developed by Hansenclever and colleagues in 1998 based on approximately 4600 patients, with seven predictive factors associated with adverse outcomes predicting freedom from progression (FFP) from 42% to 84% and overall survival (OS) from 56% to 89%. While still predictive of outcome in the modern era, survival results have improved, with the same model now associated with OS rates between 67% and 98% Importantly, there were only 5% of patients older than 60 years in this dataset. Retrospective assessments have suggested comorbidity and ADLs may be important predictors in older HL patients. More recently there has been a refinement of prognostication based on biology that has focused on tumor-associated macrophage markers (CD68 and CD163), as well as a 23-gene nanostring gene expression predictor.
Outcomes in Older Patients
Older patients with HL, typically defined as 60 years or older, have significantly inferior outcomes in comparison to younger patients in retrospective and population databases over the last decades. More recent reports from SEER have confirmed improvements in outcomes over time, but contemporary analysis from the randomized E2496 ABVD v Stanford V program continue to confirm this disparity.
One of the complex issues in this population is whether or not death is due to the underlying HL or due to competing factors. In the E2496 study, the cumulative incidence of death, including competing risks, was 23% and 30% for older patients compared to 7% and 10% for younger patients at 3 and 5 years, respectively. Death due to HL progression in older patients was 16% and 21% at 3 and 5 years, respectively. The reasons for differential outcomes in older patients are many, including disease biology, comorbidity, functional status, relative chemotherapy intensity, and toxicity.
Early-Stage Disease (Nonbulky Stage I-IIA)
Early-stage HL patients are typically younger and enjoy excellent survival, with approaches designed to minimize the long-term toxicities of associated therapy. Treatments are generally based on early-stage risk assignment as either favorable or unfavorable early-stage disease based on early-stage prognostic models. Age figures into two of the early-stage risk models as an adverse factor (EORTC age ≥ 50 and NCIC models age ≥ 40 years). Higher-dose and extended-field RT alone was historically a standard treatment option, and may be a consideration for older frail patients, but this has generally been supplanted by combined modality regimens (eg, ABVD + IFRT) in an effort to decrease the long-term toxicities of RT; these toxicities include increased heart disease, pulmonary dysfunction and secondary cancers. Latency periods for these late effects, generally 8 to 12+ years, should be a consideration in older individuals when chemotherapy is equally fraught with toxicity.
Patients With Early-Stage Favorable and Unfavorable Disease
ABVD (four cycles), developed as a less leukemogenic alternative to MOPP therapy, was established by Bonadonna and colleagues as the standard approach for early-stage disease in conjunction with IFRT (36 Gy). The HD10 German Hodgkin study group subsequently confirmed equal outcomes with ABVD × 2 cycles followed by 20 Gy IFRT for patients with no risk factors, with OS rates of 96.6% to 7.5%. MSKCC explored ABVD (six cycles) alone vs ABVD (six cycles) + IFRT/EFRT for patients with stage I, II, IIIA nonbulky disease and demonstrated comparable OS rates at 60 months of 97% versus 90% respectively (p = .08). The NCIC HD6 study demonstrated excellent outcomes for patients treated with ABVD alone if they were in CT CR following two cycles (total four cycles).
More recently, two trials in early-stage favorable patients have integrated interim PET into the treatment paradigm. The UK Rapid study explored ABVD × 3 cycles followed by functional imaging, with monitoring for patients who were PET negative (Deauville 1–2), or one additional cycle of ABVD followed by IFRT with excellent PFS (3-year PFS 93.8% for IFRT vs 90.7% with no further therapy; 3-year OS 97% vs 99.5%), sparing about 75% of patients from RT exposure. In contradistinction, the EORTC H10 trial concluded CMT resulted in fewer early progressions compared with ABVD alone, even in favorable disease with negative PET2, closing this arm early.
For patients with early-stage unfavorable disease, the HD11 trial from the GHSG established ABVD × 4 cycle followed by 30 Gy IFRT as an effective treatment option with less toxicity than BEACOPP, with 5-year PFS of 87%. The Stanford V regimen was initially developed to minimize anthracycline and bleomycin exposure and was heavily RT dependent. Subsequent investigations (E2496) comparing ABVD versus Stanford V in locally extensive and advanced-stage disease demonstrated Stanford V was not superior to ABVD and was associated in subgroup analysis with worse outcomes and more toxicity in older patients.
Advanced-Stage Disease (Stage III/IV)
For patients with advance stage HL, MOPP chemotherapy was the first successful regimen with DFS of 66% at greater than 10 years. The associated infertility and secondary malignancies (MDS and leukemia) led to a search for alternative regimens. A landmark CALGB study demonstrated ABVD alone (or alternating with MOPP), to be superior to MOPP as initial treatment for advanced-stage HL. This was confirmed in an Intergroup study, establishing ABVD as the standard of care for the last decades. Stanford V and BEACOPP are two regimens that have undergone randomized trials against ABVD with the goal of improving outcomes. The E2496 study showed no significant benefit for Stanford V versus ABVD and inferior outcomes with Stanford V for high-risk patients (IPS ≥ 3). This regimen is also associated with increased toxicity in older patients.
The intensive escalated BEACOPP regimen was compared with COPP-ABVD in the HD9 study with superior outcome for escalated BEACOPP at 1 year (OS 86% vs 75%). Importantly, a subgroup of HD9 for older patients demonstrated escalated BEACOPP to be too toxic in older patients (age > 60), and consequently, it is not recommended. Escalated BEACOPP for six cycles is currently considered an option based on the HD15 trial (rather than eight cycles or a dose intensified regimen), with OS of 95.3% but associated TRM of 4.6%. Ongoing studies have generally confirmed excellent disease outcomes with escalated BEACOPP, but improvements over ABVD are offset by secondary malignancy, toxicity, and a lack of OS benefit.
Consolidation with IFRT for patients following chemotherapy for advanced-stage disease is likely of small benefit in settings with PET negativity. Patients with PET-positive PR may benefit from additional RT, a particular consideration in older patients where salvage IFRT/ASCR may not be an option.
Second-line chemotherapy (ICE, GND) followed by HDT/ASCR for chemosensitive disease has been demonstrated to result in curative outcomes in more than 60% of patients, although this is modified by risk factors of B symptoms, extranodal sites of disease, and relapse less than 12 months from diagnosis at time of relapse. Patients with 0–1 risk factor have 5-year EFS and OS of 83% and 90%, while those with all three risk factors have EFS and OS of 10% and 25%, respectively.
Brentuximab vedotin (BV) is an antibody drug conjugate targeting CD30 with activity in relapsed and refractory CD30-positive lymphomas. Single-agent activity in relapsed disease post transplant results in ORR and CR of 75% and 34%, respectively. Maintenance BV posttransplant (AETHERA trial) improves PFS in a randomized study, without OS impact to date. Clinical trials are now incorporating BV earlier in the treatment paradigm to determine if it can improve outcomes and decrease toxicity. BV + ABVD was associated with pulmonary toxicity in a phase I trial, and consequently, ongoing efforts combine BV with AVD, eliminating bleomycin. This may be a desirable option for older patient in whom bleomycin is a frequent and, at times, fatal cause for significant pulmonary toxicity.
These outcomes must always be considered in the context of the life expectancy of patients at the time of diagnosis. In many instances, despite comorbidity, HL will represent the most immediate threat.
The CALGB 8251 trial was a prospective trial reporting outcomes with ABVD in older patients. In this analysis, patients 60 years or older had 5-year OS of 31% versus 63% for those aged 40 to 59, and 79% for those less than 40 years old.
The SHIELD study prospectively studied the VEPEMB (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone, bleomycin, prednisolone) program in older patients, with phase II data demonstrating 3-year PFS and OS of 58% and 66%, respectively, for advanced-stage patients. For early-stage patients, 74% of patients achieved CR with PFS at 3 years of 87%.
For patients to whom anthracycline-based therapy cannot be given, regimens such as ChlVVP, MOPP, and C-MOPP can be considered.
FOLLOW-UP AND SURVIVORSHIP IN NHL AND HL
Based on the revised Lugano classification for response assessment, PET-CT scan should generally be utilized at the end of treatment to assess response based on a Deauville 5-point scale. This is generally performed 6 to 8 weeks following chemotherapy or chemo-immunotherapy. CT imaging is preferred in low or variable FDG-avid histologies. A complete metabolic response, even with persistent mass, is considered complete remission and has been associated with similar outcomes. Consequently, the term complete remission, unconfirmed (CRu), introduced in the IWF is no longer utilized.
Deauville score (5-point scale) (Table 105-8) utilizes the patient’s FDG uptake in the mediastinal blood pool and liver as internal controls to assess disease response. Scores of 1-2 are generally consistent with a complete metabolic response. Scores of 3 require integration of the clinical context and whether or not the value is being used to change therapy in the setting of a clinical trial.
TABLE 105-8DEAUVILLE 5-POINT SCALE ||Download (.pdf) TABLE 105-8 DEAUVILLE 5-POINT SCALE
2—Uptake ≤ mediastinal blood pool
3—Uptake > mediastinal blood pool but ≤ liver
4—Uptake moderately > liver uptake, at any site
5—Uptake markedly higher than liver (ie, two to three times the maximum SUV in the liver) and/or new lesions
X—New areas of uptake unlikely to be related to lymphoma
Surveillance imaging in remission is increasingly discouraged, given the lack of evidence demonstrating improvement in survival and concerns over exposure to medical radiation. The clinical context is important to consider when making these decisions, as risk of relapse is greatest in the 1 to 2 years following completion of therapy for aggressive histologies. Given the long natural history of indolent lymphomas, judicious use of follow-up scans can be considered, particularly when intra-abdominal retroperitoneal disease is present. The risks of secondary malignancies for medical radiation exposure may have less impact in patients diagnosed at older age given the latency period.
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