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Biol Blood Marrow Transplant 2000; 6: 448–55. 113. Alexanian R, Dimopoulos MA, Delasalle KB, Hester J, Champlin R. Myeloablative therapy for primary resist- ant multiple myeloma. Stem Cells 1995; 13 (Suppl 2): 118–21. 114. Ghosh K, Gosavi S, Pathare A, Madkaikar M, Rao VB, Mohanty D. Low cost autologous peripheral blood stem cell transplantation performed in a municipal hospital for a patient with plasma cell leukaemia. Clin Lab Haematol 2002; 24: 187–90. 115. Hayman SR, Fonseca R. Plasma cell leukemia. Curr Treat Options Oncol 2001; 2: 205–16. 116. Hovenga S, de Wolf JT, Klip H, Vellenga E. Consolidation therapy with autologous stem cell transplantation in plasma cell leukemia after VAD, high-dose cyclophos- phamide and EDAP courses: a report of three cases and a review of the literature. Bone Marrow Transplant 1997; 20: 901–4. 117. Kosmo MA, Gale RP. Plasma cell leukemia. Semin Hematol 1987; 24: 202–8. 118. Mak YK, Chan CH, Chen YT, Lau SM, So CC, Wong KF. Consolidation therapy with autologous blood stem cell transplantation in a patient with primary plasma cell leukaemia. Clin Lab Haematol 2003; 25: 55–8. 119. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 1983; 2: 822–4. 120. Panizo C, Rifon J, Rodriguez-Wilhelmi P, Cuesta B, Rocha E. Long-term survival in primary plasma cell leukemia after therapy with VAD, autologous blood stem cell transplantation and interferon-alpha. Acta Haematol 1999; 101: 193–6. 121. Sica S, Chiusolo P, Salutari P, et al. Long-lasting com- plete remission in plasma cell leukemia after aggres- sive chemotherapy and CD34-selected autologous peripheral blood progenitor cell transplant: molecular follow-up of minimal residual disease. Bone Marrow Transplant 1998; 22: 823–5. 122. Yang CH, Lin MT, Tsay W, Liu LT, Wang CH, Chen YC. Autologous bone marrow transplantation for plasma cell leukemia: report of a case. Transplant Proc 1992; 24: 1531–2. 123. Yeh KH, Lin MT, Tang JL, Yang CH, Tsay W, Chen YC. Long-term disease-free survival after autologous bone marrow transplantation in a primary plasma cell leukaemia: detection of minimal residual disease in the transplant marrow by third-complementarity- determining region-specifi c probes. Br J Haematol 1995; 89: 914–16. Introduction Non-Hodgkin lymphoma (NHL) is a topic of increas- ing signifi cance in an aging population. According to the National Cancer Institute’s SEER program, the overall incidence of NHL increased by 75% between 1973 and 1994, or approximately 3% each year [1]. However, not only is the incidence rising, but one- half of all lymphomas are diagnosed in patients over 65 years of age, and the incidence by age keeps increasing at least until age 85 [2]. In the context of an aging population, the absolute number of patients over 65 years with lymphoma is expected to double within the next 25 years [3]. Fortunately, our understanding of lymphoma biology is also steadily growing, leading to innovative treatments that capi- talize upon this new understanding. Lymphomas are biologically heterogeneous, and for most subtypes the etiology is unknown. Although epi- demiologic factors, often incompletely understood, such as geography, environmental exposure, immu- nodefi ciency, and specifi c preconditions, play a role, there is a strong relationship between aging and the development of NHL [4–10]. To some extent this may relate to exposure and opportunity, but with aging also come aberrations in immune function and response. The heterogeneity of lymphomas extends to their clinical behavior. Although the behavior of specifi c subtypes of NHL tends to be similar regardless of age, the impact of the disease and the individual’s ability to tolerate the necessary interventions may vary. Thus, it is important to have an appreciation of the varieties of NHL and their management in an older population. Non-Hodgkin lymphoma Nicole Jacobi, Bruce A. Peterson Classifi cation and clinical evaluation In order to make appropriate clinical decisions it is vital to appreciate the differences in various subtypes of NHL. This chapter focuses on the largest group, mature B-cell lymphomas. In the past, an imperfect understanding of lymphoma biology and multiple systems of classifi cation contributed to complexity and confusion. In 1982, the International Working Formulation began to address these problems by providing a common language that bridged differ- ent nomenclatures in use throughout the world [11]. The Revised European–American Classifi cation of Lymphoid Neoplasms (REAL) [12] then integrated distinctive biological with morphological features as the forerunner of the current World Health Organization (WHO) classifi cation of Tumors of Hematopoietic and Lymphoid Tissue (Table 22.1) [13]. The WHO Classifi cation utilizes relevant mor- phologic, immunologic and genetic features to dis- tinguish entities that are biologically and clinically relevant. Upon discerning the diagnostic subtype, clinical behavior can be anticipated, an appropriate evalu- ation initiated, and management options identifi ed. The anticipated clinical behavior of each subtype can be characterized as indolent or aggressive. Indolent lymphomas, usually disseminated, may be associated with a life expectancy of several years, but often without prospect of cure. Aggressive lympho- mas, on the other hand, present no middle ground with the choice between cure-directed treatment, or palliation and an unrelenting course to death. 290 22 Blood Disorders in the Elderly, ed. Lodovico Balducci, William Ershler, Giovanni de Gaetano. Published by Cambridge University Press. © Cambridge University Press 2008. Non-Hodgkin lymphoma 291 The Ann Arbor staging system, originally developed for Hodgkin lymphoma, is an important adjunct to the WHO classifi cation in the initial evaluation of the patient with NHL (Table 22.2). There are some draw- backs to its use in NHL, but rigorous staging according to a predetermined schedule of tests has numerous advantages. Staging (1) facilitates the identifi cation of inapparent disease that might constitute a clinical threat; (2) provides assistance in deciding among therapeutic options; (3) allows an estimate of prog- nosis; (4) allows the baseline identifi cation of disease sites that can be used to assess response; and (5) establishes uniformity for patients included in clini- cal trials. Studies routinely recommended for staging and prognostic evaluation include adequate biopsies, including bone-marrow aspirates and cores, and labo- ratory and radiologic tests. Multiple bone-marrow core biopsies will more likely identify involvement because it is often focal. FDG-PET/CT fusion scans can delineate involved sites not otherwise identifi ed and clarify questionable radiographic fi ndings. However, metabolic activity may not be suffi cient in indolent lymphomas to routinely provide useful PET imaging. Laboratory studies (e.g., hemoglobin and serum LDH) aid in establishing prognosis and assess potential problems, such as organ dysfunction, hypercalemia, hyperuricemia, and spontaneous tumor lysis. In addition to histopathologic subtype and stage, there are other important factors that also contrib- ute to an estimation of prognosis. Age almost always emerges as important in prognosis and is most likely a surrogate for aggregate factors, such as comorbid- ity and functional capability [14–17]. Comorbidity is a signifi cant risk factor for shorter survival [18], and a poor performance status can largely replace advanced chronologic age as an adverse factor for the risk of treatment-related death [19]. The Comprehensive Geriatric Assessment (CGA) score may help to even better identify frail patients, but still has to be evaluated in a prospective trial [20–23]. Standard multifactorial prognostic indices that consider both host and tumor characteristics are important. The most commonly used are the International Prognostic Index (IPI) [15] and the Follicular Lymphoma International Prognostic Index (FLIPI) (Table 22.3) [17]. In 1993, the IPI was devel- oped for diffuse aggressive lymphomas, based an on analysis of patients treated with curative intent. Five easily established clinical factors provide an impor- tant tool to assess prognosis. The number of factors present (0–5) predicts complete response rates that range from 91% to 36% and fi ve-year survival between 56% and 21% (Table 22.4) [15]. Although the IPI was Table 22.1. WHO classifi cation of mature B-cell neoplasms [13]. Chronic lymphocytic leukemia/small lymphocytic lymphoma Lymphoplasmacytic lymphoma Splenic marginal zone lymphoma Extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma) Nodal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Burkitt lymphoma Table 22.2. Ann Arbor staging system for non-Hodgkin lymphoma. Stage I Involvement of a single lymph-node region or a single extralymphatic site Stage II Involvement of two or more lymph-node regions on the same side of the diaphragm with or without localized involvement of an extralymphatic site Stage III Involvement of lymph-node regions on both sides of the diaphragm with or without localized involvement of an extralymphatic site Stage IV Diffuse or disseminated involvement of one or more extralymphatic sites Presence or absence of symptoms noted with each stage designation: A, asymptomatic B, fever, night sweats, weight loss 292 Nicole Jacobi, Bruce A. Peterson not specifi cally developed for elderly patients, it dis- criminates well those at highest risk. In the indolent follicular lymphomas, it has proven more diffi cult to meaningfully identify patients at substantial risk. Although the IPI has been applied with modest suc- cess, the FLIPI may be more pertinent [17]. On the basis of fi ve factors, three groups of patients with fol- licular lymphoma can be identifi ed that have ten-year survival rates ranging from 70% to 30% (Table 22.4). Genetic features of NHL can serve as distin- guishing diagnostic or prognostic characteristics and can, in some cases, be used in the detection of inapparent disease. In follicular lymphomas the t(14;18)(q32;q21) juxtaposes BCL-2 with the immu- noglobulin heavy chain gene, and is pathogenetic [24–28]. Its presence may assist in the diagnosis or in the detection of residual disease. Additional genetic changes in follicular lymphoma, such as those involving BCL-6 [29] or altered expression of C-MYC [30], predict a higher risk of transformation. Patterns of multiple gene expression may suggest responsiveness to individual agents, such as rituxi- mab [31], or overall prognosis [32]. In diffuse large B-cell lymphoma (DLBCL) at least three major sub- types can be distinguished by microarray analysis [33–36]. It can have the molecular signature of acti- vated B cells, germinal-center B cells, or a less com- mon subtype, type 3. Those with the activated B-cell pattern have a relatively unfavorable outcome with chemotherapy [37], but this may be abrogated by the inclusion of rituximab with chemotherapy [38]. Precise molecular fi ndings may not have the same signifi cance in patients of different ages. For exam- ple, the overexpression of BCL-2 and p53 in DLBCL does not appear to have the same adverse prognos- tic signifi cance in older as in younger patients [39]. Undoubtedly, new biological features will continue to emerge, and will permit even greater refi ne- ments in classifi cation, prognosis, and treatment selection. Table 22.3. Prognostic indices for non-Hodgkin lymphoma. Follicular Lymphoma International Prognostic International Prognostic Index (IPI) [15] Index (FLIPI) [17] Factor Age Ͼ60 years ϩϩ Serum LDH Ͼ normal ϩ* ϩ* Ann Arbor Stage III–IV ϩ* ϩ* Extranodal sites Ͼ1 ϩ — Performance status у2 ϩ* — Hemoglobin Ͻ12 gm/L — ϩ* Nodal sites Ͼ4 — ϩ* Risk group Number of factors a Number of factors a Low 0–1 (0) 0–1 (1) Low/intermediate 2 (1) — Intermediate — 2 (2) High/intermediate 3 (2) — High 4–5 (3) у3 (у3) * Only those factors identifi ed by asterisk should be used if index restricted to patients over 60 years. a Number of factors in parentheses is used if index restricted to patients over 60 years. Non-Hodgkin lymphoma 293 Clinical management of indolent B-cell lymphomas Indolent lymphomas, despite important differences between subtypes, are characterized by slow pro- gression and, often, the absence of any symptoms for prolonged periods of time. These lymphomas account for 30% of adult NHL, but one subgroup, fol- licular lymphoma, makes up the great majority and is second in frequency only to DLBCL [11,13,40,41]. The other subtypes, including small lymphocytic, lymphoplasmacytic, and marginal zone lympho- mas, are far less common. Small lymphocytic lymphoma is related to chronic lymphocytic leuke- mia, which is discussed in Chapter 24. Follicular lymphoma Follicular lymphomas have been extensively studied, and often serve as the prototype for management of other indolent lymphomas. Lymphadenopathy that may be modest and long-standing is most often the presenting fi nding. Patients are typically in their sixth or seventh decade. Most patients are asympto- matic, and less than a third will have B symptoms. Involvement of the bone marrow can be detected Table 22.4. Outcome by risk group in prognostic indices. Distribution of Survival patients (%) 2 year (%) 5 year (%) 10 year (%) International Prognostic Index [15] All patients Risk group Low 35 84 73 — Low/intermediate 27 66 51 — High/intermediate 22 54 43 — High 16 34 26 — Age-adjusted Ͼ60 years Risk group Low 18 80 56 — Low/intermediate 31 68 44 — High/intermediate 35 48 37 — High 16 31 21 — Follicular Lymphoma International Prognostic Index [17] All patients Risk group Low 36 — 91 71 Intermediate 37 — 78 51 High 27 — 52 36 Age-adjusted Ͼ60 years Risk group Low 20 — 85 70 Intermediate 32 — 70 45 High 48 — 45 30 294 Nicole Jacobi, Bruce A. Peterson morphologically in up to 65%, but even more patients may have disseminated disease demon- strated by sensitive molecular tests. Fortunately, the fi nding of lymphoma in the bone marrow has little impact on prognosis. Nearly 85% will be stage III–IV. The architecture of the lymph node shows a follicu- lar or nodular pattern, and based on the proportion of large cells in the malignant nodules, follicular lymphomas can be graded 1 through 3 [13,41]. Grade 3 generally has more rapid clinical growth [42]. The t(14;18)(q32;q21) can be detected in 90% of the cases by either classical banded cytogenetics or molecular techniques [24,43]. The general approach to patients with follicular lymphoma does not need to vary because of age. Since the disease is often indolent, patients asymp- tomatic, and treatments generally not curative, ther- apy can often be deferred until clinically necessary without jeopardizing the patient’s prognosis while enhancing quality of life [44–50]. Median survival is eight to ten years. However, the rare patient with localized disease may have prolonged disease-free survival following irradiation [51,52]. In view of this possibility, whether patients with localized disease should be observed or treated should be individual- ized [44,49,51]. When treatment is necessary in the patient with advanced disease, a wide range of possibilities exists, extending from the use of single drugs (e.g., alkylat- ing agents [53–56], nucleoside analogs [57–62], rituximab [63–67]) to modest combinations, such as CVP (cyclophosphamide, vincristine, prednisone) [54,56,68] or combinations based on fl udarab- ine [62,69–73], to those combinations commonly reserved for patients with aggressive lymphomas, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) [55,74–76]. Clinical trials in follicular lymphomas largely have not focused special attention on the elderly. Fortunately, this has not been a major issue because even the most innocuous therapies are likely to be initially as effective as more aggressive treatments. The use of a single alkylator, either chlorambucil or cyclophosphamide, is as effective for most patients as combinations such as CVP [54,56,68] or CHOP [55,76], and may induce a signifi cant response in 90% of patients. As single agents, these drugs are generally very well tolerated in old and young alike, but have toxicities (e.g., hemorrhagic cystitis and myelosuppression) that must be considered. Fludarabine is the most commonly used nucleoside analog and is also generally well tolerated [60,77,78]. It may not be as active as alkylating agents and may induce a more lasting impairment of the immune system. The use of fl udarabine also has been associ- ated with a heightened risk of earlier transformation [79,80], and both alkylating agents and nucleoside analogs have been associated with secondary leuke- mias [81–84]. Any of these approaches can yield a meaningful response, but relapse is almost inevita- ble. When the disease returns and treatment is again necessary, depending on the quality of the original response, re-treatment with the original therapy may be appropriate. Rituximab, initially introduced for the relapsed patient, can also be useful as initial therapy. Although response rates appear to be lower than with com- monly used chemotherapies, an objective response can be obtained in approximately 50–60% of patients, with little toxicity [64–67]. The median time to pro- gression is about 18–20 months. A strategy of main- tenance therapy, repeating rituximab at specifi ed intervals, leads to longer remissions, but whether this is the best overall strategy is still not settled [64,65]. Success with rituximab in various settings has led to studies of its inclusion as a component of drug combinations. However, since controlled clinical trials are essential to clarify the benefi ts of new therapies, the role of rituximab in combi- nation is not established. In a randomized study, the addition of rituximab to CVP (R-CVP) as initial treatment resulted in an improved response rate and prolonged time to progression [85]. However, there was not a signifi cant increase in survival. In relapsed patients, a small phase III study assessed fl udarabine, cyclophosphamide, and mitoxantrone with (R-FCM) or without rituximab (FCM) [70]. An improved response rate (94% vs. 70%, p ϭ 0.011) and progression-free survival (median Ͼ36 months vs. 21 months, p ϭ 0.0139) were seen with R-FCM, Non-Hodgkin lymphoma 295 but survival was not signifi cantly affected by the addition of rituximab. In a study of fl udarabine plus mitoxantrone (FM) versus CHOP, each with or without rituximab, the complete response rate was higher with FM. However, again this did not translate into an improvement in progression-free or overall survival [86]. Radiolabelled monoclonal antibodies, I-131 tositumomab and ibritumomab tiuxetan, have also become available for use in fol- licular lymphomas, and hold promise. Their role in the overall scheme of management of follicular lym- phomas remains to be determined [87–90]. For the older patient with follicular lymphoma who requires treatment, the choice is myriad. Certain interventions may offer higher rates of ini- tial response, sometimes with increased toxicity, cost, or inconvenience. Occasionally, this translates into an improvement in time to failure, but almost never to an extension of survival. Thus, a strategy for patients needing treatment begins with the least burdensome therapy associated with an acceptable response rate, providing meaningful intervention while limiting unnecessary side effects, incon- venience, and risk. This does not eliminate future options, and more toxic or risky treatments are reserved for when necessary. Lymphoplasmacytic lymphoma Lymphoplasmacytic lymphoma, accounting for less than 2% of all adult lymphomas, presents most commonly in males and almost always after 50 years of age [13,40,91,92]. Although a monoclonal IgG or IgA protein may be present, classically, this sub- type is accompanied by monoclonal IgM and called Waldenström macroglobulinemia. Frequent sites of involvement include nodes, spleen, and the gas- trointestinal tract. The marrow is usually involved and up to 80% of patients will be stage IV. With extensive marrow infi ltration, anemia and pancyto- penia are common. Lymphoplasmacytic lymphoma may be associated with amyloidosis. Prior infection with hepatitis C may play a role in pathogenesis. The systemic symptoms of fevers, night sweats, and weight loss are infrequent. Fatigue, often related to anemia, is a common symptom. Hypercalcemia, as a result of lytic bone disease, cryoglobulinemia, and cold agglutinins can each lead to manifesta- tions. Most notably, IgM forms large pentameric aggregates that can increase the serum viscosity to the extent that clinical hyperviscosity, mucosal bleeding, fatigue, mental status changes, and blurred vision are seen in 15% of patients. Increased viscosity can lead to strokes, cardiac ischemia, and high-output cardiac failure. Unfortunately, meas- ured serum viscosity does not correlate very well with clinically signifi cant hyperviscosity [93,94]. The median life expectancy of an individual with Waldenström macroglobulinemia is 5–7 years. How- ever, extensive marrow replacement is adverse and predicts a median survival of a year or less [95]. Other correlates of a poorer prognosis are hemoglobin less than 10 gm/dL, very high monoclonal peak, weight loss, and age over 60 years. The t(9;14)(p13;q32) is a frequent cytogenetic fi nding, but does not seem to carry prog- nostic signifi cance [24,91,96]. As with other indolent B-cell lymphomas, asymp- tomatic patients with lymphoplasmacytic lymphoma who are not anemic or experiencing signifi cant problems may be observed without initial therapy [91,93,94]. Close monitoring for disease progression, renal and metabolic derangements, and potential manifestations of hyperviscosity is required. Once the necessity of treatment is established, many of the same options appropriate for follicular lymphoma can be considered. An alkylating agent, chlorambucil, is a standard fi rst choice and results in partial responses for 50–75% of patients. The addition of prednisone is not benefi cial unless needed for an immunologic problem. Combinations such as CHOP are also not more useful than single agents in the initial phase of treatment. Although the nucleoside analogs, fl udara- bine [77,97] and 2-chlorodeoxyadenosine [95,98], produce response rates similar to chlorambucil, 2Ј-chlorodeoxyadenosine has been reported to more rapidly reduce the monoclonal protein, dropping the level by more than half within two months. Newer treatments [93,94,98,99] include rituximab, inter- feron alpha, thalidomide, bortezomib, and in highly selected cases with problematic disease, high-dose 296 Nicole Jacobi, Bruce A. Peterson therapy with stem-cell transplant [100,101]. The use of rituximab, active in 30–40% of patients, may be asso- ciated with a rapid rise in serum IgM precipitating manifestations of hyperviscosity [102,103]. For those patients presenting with hyperviscosity syndrome, plasmapheresis can almost immediately reduce the monoclonal protein and rapidly improve the clini- cal situation. In this setting chemotherapy should be instituted soon after plasmapheresis to control the disease over the longer term. Marginal zone lymphomas There are three varieties of marginal zone lym- phoma (Fig. 22.1) identifi ed in the WHO classifi ca- tion: splenic, nodal, and extranodal [13]. Each has unique characteristics that may infl uence the clini- cal approach. Splenic marginal zone lymphoma Splenic marginal zone lymphoma is rare [40,104–108]. It occurs most frequently in women and at a median age of 68 years. In some cases it has been associated with chronic hepatitis C infection, and treatment for hepatitis C with interferon has been reported to result in improvement [109]. Splenomegaly is the unify- ing fi nding and accounts for most of the problems. Fatigue from a moderate anemia caused by splenic sequestration is common. Substantial lymphad- enopathy is unusual, and B symptoms are very rare. Peripheral blood involvement, sometimes with cells that have small cytoplasmic villous projections, is fre- quent, but usually modest. A monoclonal gammopa- thy is seen in half of the patients. The t(11;14)(q13;q32), a translocation more commonly associated with mantle cell lymphoma, and allelic loss of 7(q21–32) have been reported, but a characteristic cytogenetic abnormality has not been described. Although modest chemotherapy may be helpful [110–112], most patients in need of treatment are best served by splenectomy [105,107,109,112]. This approach corrects symptoms in the great majority of patients and the benefi ts can be quite durable. Median survival is approximately nine years. Nodal marginal zone lymphoma Nodal marginal zone lymphoma is only slightly more common than the splenic variety, accounting for less than 2% of adult NHL [13,40,113,114]. It also affects more women than men, and patients at diagnosis have a median age of 64 years. Lymphadenopathy, especially of peripheral nodes, is common, and the spleen is enlarged in most patients. When nodes are involved in a setting of extranodal disease, the nodes should be considered an extension of the extranodal process. Nearly three-quarters will have advanced- stage disease, two-thirds will have splenomegaly, and one-third bone-marrow involvement. There are no unique diagnostic cytogenetic or molecular abnormalities. The prognosis is slightly worse than that of other indolent B-cell lymphomas; the median survival is approximately fi ve years. However, the approaches used in follicular lymphomas, observation without initial therapy in asymptomatic patients and inter- ventions tied to particular situations, are still most appropriate [115,116]. In the uncommon setting of Figure 22.1 Marginal zone lymphoma: neoplastic marginal zone cells with moderately abundant cytoplasm have plasmacytoid appearance. Kadin, M., ASH Image Bank 2004: 101238. Copyright American Society of Hematology. All rights reserved. See color plate section. Non-Hodgkin lymphoma 297 localized disease, involved-fi eld irradiation may be considered. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) The MALT lymphomas (Figs. 22.2, 22.3) are especially interesting because an etiology or predisposition can often be identifi ed [13,117–119]. Many occur in sites where chronic infectious, autoimmune, or infl ammatory stimuli pre-exist. The relationship between gastrointestinal infection with Helicobacter pylori and some cases of gastric MALT lymphoma is well established [120–122]. More recently, evidence of a role for Borrelia burgdorferi and Chlamydophila psittaci has been reported in the evolution of cuta- neous [122–124] and ocular adnexal [117] MALT lymphomas, respectively. As fi rst demonstrated for H. pylori, and now for both B. burgdorferi and C. psittaci, treatment directed at the bacteria may cause tumor regression. MALT lymphomas affect a wide range of primary sites in addition to those noted above, including thyroid, salivary gland, breast, and lung [13,40,125– 128]. Together, they make up about 8% of all lym- phomas. In keeping with the potential etiologic role of chronic infl ammation, Hashimoto’s thyroiditis often precedes MALT lymphomas of the thyroid, and Sjögren’s syndrome may precede MALT lym- phomas of the salivary glands. Most patients are over 60 years of age, and presenting symptoms are non- specifi c but relate directly to the tissue involved. Thus, in gastric MALT lymphomas, symptoms associated with gastritis or ulcers may be present. Ocular adnexal involvement may lead to mild eye discomfort, visual blurring, conjunctival thickening, or small tumor nodules. Chronic respiratory symp- toms may be seen with pulmonary disease. MALT lymphomas arising at other sites usually present with slowly growing masses. One-half of MALT lymphomas are gastric, and evidence for H. pylori should be sought, because, if present, appropriate antibiotics plus proton pump inhibitors can usually eradicate the organism, and if H. pylori is eliminated, about 80% of patients will have subsequent tumor regression and may not need other therapy [120–122]. Since 80–90% of gas- tric MALT lymphomas are isolated, if antibiotics fail or the tumor is not associated with H. pylori, gastric irradiation can still be curative [129,130]. The best approach to localized extranodal lympho- mas at other sites may involve the use of irradiation, since there is not yet suffi cient data to recommend antibiotics as fi rst-line therapy [131,132]. However, Figure 22.2 Gastric MALT lymphoma: gross pathology. Normal gastric mucosa disrupted by MALT lymphoma. Kadin, M., ASH Image Bank 2003: 100693. Copyright American Society of Hematology. All rights reserved. See color plate section. Figure 22.3 Gastric MALT lymphoma: marginal zone cells colonize and obliterate germinal centers of reactive B-cell follicles. Kadin, M., ASH Image Bank 2003: 100693. Copyright American Society of Hematology. All rights reserved. See color plate section. [...]... Fludarabine in combination with idarubicin as treatment of untreated and relapsed low-grade lymphoma 74 75 76 77 78 79 80 81 82 83 Preliminary results of a multicenter phase II study Blood 1999; 94 (Suppl 1): 95a Czuczman MS, Grillo-Lopez AJ, White CA, et al Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy J Clin Oncol... for ATLL remains unsatisfactory Single-agent chemotherapy is generally ineffective Combination chemotherapy regimens involving anthracyclines can induce fairly high response rates but patients invariably relapse and succumb to their disease The lymphoma study group in Japan completed a trial involving 96 patients treated with three alternating combination regimens consisting of vincristine, cyclophosphamide,... Full-dose CHOP chemotherapy combined with granulocyte colony-stimulating factor for aggressive non-Hodgkin’s lymphoma in elderly patients: a prospective study Ann Hematol 2001; 80: 602–6 Zinzani P Pavone E, Storti S, et al Randomized trial , with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-Hodgkin’s lymphoma Blood 19 97; 89: 3 974 –9... THP-COPBLM (pirarubicin, cyclophosphamide, vincristine, prednisone, bleomycin and procarbazine) regimen combined with granulocyte colony-stimulating factor (G-CSF) for non-Hodgkin’s lymphoma in elderly patients: a prospective study Leukemia 19 97; 11: 18 17 20 142 Niitsu N, Umeda M Response and adverse drug reactions to combination chemotherapy in elderly patients with aggressive non-Hodgkin’s lymphoma: comparison... in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule Blood 2004; 103: 4416–23 Hainsworth J, Litchy S, Shaffer D, Lackey V, Grimaldi M, Greco F Maximizing therapeutic benefit of Non-Hodgkin lymphoma 66 67 68 69 70 71 72 73 rituximab: maintenance therapy versus re-treatment at progression in patients with indolent... assess the true utility of these drugs However, none appears to eliminate the risk of cardiomyopathy Non-Hodgkin lymphoma Table 22.5 Selected clinical trials in elderly patients with diffuse aggressive non-Hodgkin lymphoma Median age (range in years) Complete response rate Overall survival rate 72 76 70 (60–82) 71 (60–84) 49% 31% (p ϭ 0.03) 42% @ 3 years 26% @ 3 years (p ϭ 0.029) 60 60 74 (70 –93) 76 (70 –93)... Hernandez AM, Levine AM, Sheibani K Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma) Semin Hematol 1999; 36: 128–38 115 Berger R, Felman P Thieblemont C, et al Non-MALT , marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients Blood 2000; 95: 1950–6 116 Bertoni F, Zucca E State-of -the- art therapeutics: marginal-zone lymphoma J Clin Oncol 2005;... 45% 27% (p ϭ 0.06) 65% @ 2 years 30% @ 2 years (p ϭ 0.004) CHOP CHOPϩG-CSF 192 1 97 73 (65–90) 72 (65–90) 55% 52% (p ϭ 0.63) 22% @ 5 years 24% @ 5 years (p ϭ 0 .76 ) Tilly et al [149] CHOP ACVBP 312 323 65 (61–69) 65 (61–69) 56% 58% (p ϭ 0.5) 38% @ 5 years 46% @ 5 years (p ϭ 0.036) Pfreundschuh et al [150] CHOP-21 CHOP-14 CHOEP-21 CHOEP-14 178 172 170 169 (61 75 ) (61 75 ) (61 75 ) (61 75 ) 60% 76 % 70 % 72 %... Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Group D’Etude des Lymphomes Folliculaires J Clin Oncol 19 97; 15: 1110– 17 Horning SJ, Rosenberg SA The natural history of initially untreated low-grade non-Hodgkin’s lymphomas N Engl J Med 1984; 311: 1 471 –5 Portlock CS, Rosenberg SA No initial therapy... 39: 77 –85 Goy A, Younes A, McLaughlin P et al Phase II study , of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma J Clin Oncol 2005; 23: 6 67 75 O’Connor O, Wright J, Moskowitz C, et al Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma J Clin Oncol 2005; 23: 676 –84 . third-complementarity- determining region-specifi c probes. Br J Haematol 1995; 89: 914–16. Introduction Non-Hodgkin lymphoma (NHL) is a topic of increas- ing signifi cance in an aging population. According to the. et al. [150] CHOP-21 178 (61 75 ) 60% 41% @ 5 years CHOP-14 172 (61 75 ) 76 % 53% @ 5 years (p Ͻ 0.001)* CHOEP-21 170 (61 75 ) 70 % 45% @ 5 years (p ϭ 0.109)* CHOEP-14 169 (61 75 ) 72 % 50% @ 5 years. about 30% [ 177 , 178 ]. Unfortunately, evi- dence that more intensive therapies such as CHOP are particularly benefi cial when used as initial treat- ment is weak [ 170 , 173 , 174 ], and the importance