Waldenström's macroglobulinemia

Best Practice & Research Clinical Haematology Vol. 18, No. 4, pp. 747–765, 2005 doi:10.1016/j.beha.2005.01.028 available online at http://www.sciencedirect.com

16 Waldenstro¨m’s macroglobulinemia Meletios A. Dimopoulos* Professor of Medicine, Department of Clinical Therapeutics, University of Athens School of Medicine, 227 Kifissias Avenue, 14561 Kifissia, Athens, Greece

Athanasios Anagnostopoulos Instructor of Medicine, Department of Clinical Therapeutics, University of Athens School of Medicine

The diagnosis of Waldenstro¨m’s macroglobulinemia (WM) requires evidence of bone-marrow infiltration by lymphoplasmacytoid lymphoma and detection of serum monoclonal protein of IgM type. The normal counterpart of the WM malignant cell is believed to be a postgerminal-center B cell. The clinical manifestations and laboratory abnormalities associated with WM are related to direct tumor infiltration and to the amount and specific properties of IgM. Asymptomatic patients should be followed without treatment. When treatment is indicated, the three main choices for systemic frontline treatment are chlorambucil, the nucleoside analogues fludarabine or cladribine and the monoclonal antibody rituximab. There is evidence that high-dose therapy with autologous stem-cell transplantation is effective even in patients with advanced and resistant disease. Patient’s age, hemoglobin and serum b2-microglobulin before treatment are important prognostic variables which correlate with survival. Keywords: Waldenstro¨m’s macroglobulinemia; diagnosis; treatment; prognosis.

EPIDEMIOLOGY AND ETIOLOGY Waldenstro¨m’s macroglobulinemia (WM) is the result of the clonal proliferation of lymphocytes that produce monoclonal immunoglobulin M (IgM). This disease was originally described in 1944 by Jan Waldenstro¨m and is considered to correspond to the lymphoplasmacytoid lymphoma as defined by the World Health Organization (WHO) classification system.1,2 Waldenstro¨m’s macroglobulinemia is approximately 10–20% as common as multiple myeloma, and there is a slight male preponderance. The median age of the affected patients is about 65 years, and the disease is significantly more common among whites than blacks. The rates for WM are comparable to those for hairy cell leukemia.3 * Corresponding author. Tel.: C30 210 3381541; Fax: C30 210 8131383. E-mail address: [email protected] (M.A. Dimopoulos). 1521-6926/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

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The etiology of WM is unknown. A possible role for genetic factors has been suggested by reports of familial clustering of WM.4 The role of environmental factors in WM is undetermined.5 A possible link between hepatitis C virus and WM has been suggested, but the results are so far inconclusive because of small samples of patients.6 Despite earlier indications of detection of Kaposi’s sarcoma-associated herpervirus in the bone marrow of patients with WM, more recent data are not conclusive.7 PATHOLOGY Waldenstro¨m’s macroglobulinemia always involves the bone marrow. The bonemarrow smear usually shows a diffuse proliferation of small lymphocytes, plasmacytoid lymphocytes (cells with abundant basophilic cytoplasm, but lymphocyte-like nuclei) and plasma cells.8 Dutcher bodies, which represent periodic acid-Schiff-positive intranuclear and intracytoplasmic inclusions, are often seen. A recent study reported excess mast cells in 72% of bone-marrow biopsies from patients with WM.9 The extent of bone-marrow infiltration is more adequately assessed with a biopsy. In a recent study, a diffuse pattern of infiltration was documented in 58% of patients and an interstitial pattern in 32%. In the remaining patients the infiltration pattern was nodular (6%) or paratrabecular (4%). Increased reticulin staining and mast-cell hyperplasia were observed in 67 and 56% of patients, respectively.10 BIOLOGY The normal counterpart of the WM malignant cell is believed to be a post-germinalcenter B cell. This indication is supported by a post-germinal-center immunophenotypic profile which includes the expression of the pan-B-cell markers CD19, CD20, CD22, CD79 and FMC7. In most cases there is no expression of CD10 or CD23, whereas CD5 is expressed in 5–20% of cases.10 Clonal sIg expression is always demonstrated. The levels of sIg expression range from moderate to strong, corresponding to that of a mature B cell prior to plasma-cell differentiation. Moreover, in contrast to plasma cells, these lymphocytes are CD138K and lack or show dim CD38 expression.11,12 With the use of variable region (V) gene analysis, there is evidence that VH genes are somatically mutated in WM. Furthermore, there is no evidence for any intraclonal variation in VH sequence.13 These observations place the cell of origin as a mature IgMC B cell that arises at a stage where mutational activity has ceased, and provide further support for origin from a cell that has exited the germinal center.14,15 Limited cytogenetic studies have been performed in WM, and karyotypic analysis usually yields normal metaphases.16,17 Unlike other B-cell lymphomas, the clonal cells of WM do not have translocations that involve the immunoglobulin heavy chain locus at chromosome 14. Furthermore, analysis of 14q32 by fluorescence in situ hybridization (FISH) and southern blot in WM indicate the absence of IgH rearrangements, confirming absence of isotype switch events by deletional recombination.17 By contrast, IgM myelomas typically exhibit 14q32 rearrangements with t (11;14) predominating.18 The only recurrent abnormality in WM is deletion of the long arm of chromosome 6, but its role in the pathogenesis of the disease has not yet been elucidated. Current research is focusing on studies of transcriptional and proteomic profiles of tumor cells in WM. Such studies are attempting to define cascades mediating proliferation, survival and drug resistance in WM, to identify molecular markers for

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diagnosis, prognosis and treatment monitoring, and to perform comparative proteomic profiling studies of WM cells and of other B-cell malignancies.19,20

CLINICAL AND LABORATORY FEATURES The clinical manifestations and laboratory abnormalities associated with WM are related to direct tumor infiltration and to the amount and specific properties of monoclonal IgM. The malignant cells divide slowly and can disseminate throughout the reticuloendothelial system and other tissues where B lympocytes recirculate. Several manifestations of WM are due to the unique properties of monoclonal IgM, including its large size, high carbohydrate content, and capacity to bind to other components of the blood and other tissues. Monoclonal IgM may behave as an autoantibody as a cryoglobulin or can have cold-agglutinin activity.21,22 Monoclonal IgM can interact with several coagulation factors and can affect platelet function, resulting in prolonged clotting time and bleeding time, respectively.21,22 Thus, the clinical and laboratory manifestations of WM can be variable and depend on which property of IgM predominates in individual patients. General symptoms and signs The most common symptoms are weakness and fatigue, usually secondary to anemia. B symptoms such as weight loss, excessive sweating and low-grade fever affect a quarter of patients (Table 1). Hepatomegaly, splenomegaly and lymphadenopathy occur in 15–30% of patients each. In some patients symptoms and signs of peripheral neuropathy, of cryoglobulinemia or of cold agglutinin disease may predominate (Table 1).23,24 Laboratory findings Some degree of anemia is present at diagnosis in the majority of patients with symptomatic WM (Table 2). Blood smears are typically normochromic and normocytic, and rouleau formation is usually found. The anemia is primarily due to bone-marrow infiltration but also to dilutional effect due to plasma volume expansion caused by Table 1. Clinical features and complications before initiation of treatment. Number of patients Median age (years) Range Male/female Percentage of patients with: B symptoms Splenomegaly Lymphadenopathy Hyperviscosity Peripheral neuropathy Cryoglobulinemia Cold agglutinin anemia Amyloidosis

176 68 27–88 102/74 18 37 26 19 8 7 3 2

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Table 2. Laboratory features before initiation of treatment. Number of patients Percentage of patients with Hemoglobin !12 g/dL Hemoglobin !10 g/dL Platelet count !150!106/Dl Platelet count !100!106/dL White blood cell count !4000 Lymphocyte count O5000 Monoclonal light chain k l Serum monoclonal protein g/dL Median Range Serum albumin!4.0 g/dL Serum albumin!3.5 g/dL Serum b2-microglobulin O3 mg/dL

176 84 51 27 11 15 12 74 26 3.4 0.3–11.7 68 40 64

serum IgM. In some patients the monoclonal IgM has cold agglutinin activity that may result in chronic hemolysis with acute exacerbations related to cold exposure.25 Occasional patients may present or develop autoimmune hemolytic anemia. The leukocyte count is usually normal, but mild lymphocytosis is not uncommon and monoclonal lymphocytes are detected with flow cytometry in the blood of virtually all patients. Some patients present with moderate to severe leucopenia (Table 2). Mild thrombocytopenia occurs in one third of patients, but severe thrombocytopenia is unusual (Table 2). Renal and liver function tests are usually normal, hyperuricemia is common and hypercalcemia is detected in !5% of patients.23,26 In some patients hypocholesterolemia is evident at diagnosis. All patients have a serum monoclonal protein which usually migrates in the gamma region. The amount of serum monoclonal protein should be evaluated from the serum protein electrophoresis strip rather than nephelometry, which may overestimate the concentration of serum IgM and must be confirmed by immunofixation. The light chain of the monoclonal protein is k in 70–80% of patients (Table 2). Uninvolved immunoglobulins are less frequently and less markedly depressed than in multiple myeloma.23 The presence of cold agglutinins or cryoglobulins may affect determination of serum monoclonal protein levels and therefore testing for these abnormalities should be performed at diagnosis.27 Bence Jones proteinuria is frequently present but exceeds 1.0 g/day in only 3% of patients.23 Serum b2-microglobulin exceeds the upper limit of the reference rate (3 mg/L) in most patients with symptomatic WM (Table 2). Blood or serum viscosity should be measured if the patient has signs or symptoms of hyperviscosity syndrome. Blood viscosity is best measured at low shear rates.28 Hyperviscosity syndrome Blood hyperviscosity occurs at diagnosis in 10–30% of patients with WM. IgM proteins are large, asymmetric molecules that are 80% intravascular. Thus, an increased concentration of those proteins, which may form aggregates and may bind water through their

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carbohydrate component, results in an increased osmotic pressure, an increase in the resistance to blood flow and impaired transit through the microcirculation.29 The hyperviscosity syndrome is characterized by chronic bleeding from the nose, the gums, and less commonly from the gastrointestinal tract. Patients complain of headache, tinnitus, vertigo, impaired hearing or ataxia. Ocular symptoms include blurring or loss of vision, and funduscopic examination may reveal distended, ‘sausageshaped’ retinal veins, flame-shaped hemorrhage, or papilledema. If viscosity continues to rise, edema, high-output heart failure, somnolence, stupor and coma may occur. Caution is required with blood transfusions because transfusion of red blood cells (RBCs) may exacerbate hyperviscosity and may precipitate heart failure. Most patients develop symptoms when the serum viscosity is more than 4 centipoise (normal values:1.4–1.8cp), but the symptomatic threshold varies from patient to patient. Most patients with symptoms and signs of hyperviscosity have a serum monoclonal protein above 4 g/dL. Furthermore, it appears that interactions of monoclonal protein with other plasma proteins and cells are more important for this process than the concentration of IgM per se.30 Cryoglobulinemia Cryoglobulins are serum proteins or protein complexes that undergo reversible precipitation at low temperatures. In 10–20% of patients with WM, the monoclonal IgM can behave as a type I cryoglobulin, but clinically evident cryoglobulinemia occurs in less than 5% of patients.10,26 Symptoms result from impaired blood flow in small vessels and include Raynaud’s phenomenon, ischemia or even necrosis of nose tip, ears, fingers, toes, malleolar ulcers, palpable purpura and urticaria.31 The antibody activity of monoclonal IgM against polyclonal IgG forms the basis for type II cryoglobulinemia. This is an immune complex disease characterized by vasculitis affecting small vessels. The clinical manifestations may include purpura, arthralgias, and Raynaud’s phenomenon, as well as involvement of glomeruli, liver and peripheral nerves. Renal involvement is characterized by a membranoproliferative glomerulonephritis which can cause renal failure if left untreated.32 Cold agglutinin hemolytic anemia In fewer than 10% of patients with monoclonal IgM, the abnormal protein reacts with specific RBC antigens at temperatures below 37 8C to produce a chronic hemolytic anemia. The hemolysis is usually mild, extravascular, and associated with a markedly elevated cold agglutinin titer (O1:1000), especially when tests are conducted at low temperatures. The protein is usually IgM k, and its most common target is the Ia antigen.33 The best explanation for the pathogenesis is that conformational changes that occur in the RBC membrane at low temperatures allow epitopes ‘invisible’ at 37 8C to become more accessible to IgM antibodies.34 Neurological abnormalities Of patients with WM, 5–20% present with or develop symptoms and signs suggestive of a peripheral polyneuropathy. This complication has been also described in individuals with monoclonal IgM but without evidence of overt lymphoma. IgM-related polyneuropathy is composed of an immunochemically and clinically heterogeneous

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group of neuropathies in which the monoclonal IgM appears to be an antibody against various glycoproteins or glycolipids of the peripheral nerve. In roughly half of these patients, the monoclonal protein (predominantly IgMk) is directed against carbohydrate epitopes of myelin-associated glycoprotein (MAG). Anti-MAG antibodies may also exhibit reactivity with other glycoproteins or glycolipids that share antigenic determinants with MAG. MAG-reactive polyneuropathy is predominantly a demyelinating sensorimotor process and exhibits a chronic, slowly progressive course. Direct immunofluorescence usually shows IgM deposits at the periphery of the myelin sheath, and sural nerve biopsy demonstrates a diminished number of myelinated axons.35,36 In the remaining 50% of patients, the peripheral neuropathy is MAG-non-reactive. In such patients the IgM may react with various gangliosides, with GD1b or GM1 glycolipids, with sulfatides or chondroitin sulfate. In several patients, however, IgM does not recognize a known antigen. Patients with MAG-non-reactive polyneuropathies usually have a sensory neuropathy (demyelinating or axonal), but some patients may have a predominantly motor axonal neuropathy. Finally, WM patients may develop a peripheral neuropathy secondary to cryoglobulinemia or to amyloidosis. Peripheral nerve dysfunction may also occur as a consequence of direct infiltration of the peripheral nerves by malignant cells.37 The central nervous system is rarely involved in WM. The Bing-Neel syndrome consists of headache, vertigo, impaired hearing, ataxia, nystagmus, diplopia, and eventually coma. This syndrome is due to long-standing hyperviscosity that causes altered vascular permeability, permeation of the white matter by IgM, perivascular infiltration of lymphoplasmacytoid cells, and eventually multifocal leukoencephalopathy.38 Amyloidosis Deposition of monoclonal light chain as fibrillar amyloid deposits (AL amyloidosis) has been occasionally reported in WM. In our series, 3% of patients with WM presented with amyloidosis.39 In a large series from Mayo Clinic, amyloidosis developed in 2% of patients with monoclonal IgM. Among those patients, 21% had WM. Organs more commonly affected by the amyloid deposition were the heart (44%), the peripheral nerves (38%), the kidneys (32%), the soft tissues (18%) and the liver (14%). The incidence of cardiac and pulmonary involvement appeared higher in patients with monoclonal IgM than with other immunoglobulin isotypes.40 Renal involvement In contrast to multiple myeloma, renal tubular abnormalities are rare in macroglobulinemia. This is probably due to the lower amount of Bence Jone proteinuria and to the rarity of hypercalcemia in WM. However, glomerular abnormalities are more frequently seen in WM than in myeloma. The IgM macromolecule is more susceptible to being trapped in the glomerular loops, to precipitate and to form subendothelial deposits of aggregated IgM proteins that occlude the glomerular capillaries.41 Such patients may present with uremia, dehydration and non-selective proteinuria. This complication can be completely reversed with plasmapheresis.42 Occasional patients have developed nephritic or nephrotic syndrome because the IgM may behave as an antibody against the glomerular basement membrane and may cause an immunemediated glomerulonephritis.43 Finally, in some patients a direct lymphoplasmacytic infiltration of the kidneys has caused renal or peripheral masses.44

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Pulmonary involvement Of patients with WM, 3–5% present with or develop lung disease consisting of diffuse pulmonary infiltrates, lung masses, or pleural effusion.45 It should be noted that lymphoplasmacytic lymphoma of the lung without bone-marrow involvement but with IgM production has been also described.46 Cutaneous involvement IgM monoclonal gammopathy has been associated with urticarial skin lesions (Schnitzler syndrome).47 Firm, translucent, flesh-colored papules and nodules on the extensor surface of the extremities have been reported and are called ‘macroglobulinemia cutis’. Biopsy and immunohistochemistry have revealed amorphous IgM deposits in the dermis, called ‘storage papules’, without evidence of malignant infiltration.48 Finally occasional patients have developed vesiculobullous eruptions consistent with paraneoplastic pemphigus or presented with a skin fragility similar to that seen in epidermolysis bullosa acquisita. In such cases immunofluorescence demonstrates linear deposition of monoclonal IgM along the skin basement membrane.49 Involvement of the gastrointestinal tract Malignant infiltration of the stomach and the bowel has been reported.50 In occasional patients, deposition of monoclonal IgM in the lamina propria and/or submucosa of the intestine may be associated with diarrhea, malabsorption and gastrointestinal bleeding.51 Eye involvement The most common ocular manifestations of WM occur in the context of hyperviscosity syndrome and are usually confined to the retina. Malignant infiltration of the orbit, the conjunctiva and the vitreous have been reported.52 DIAGNOSTIC CRITERIA AND DIFFERENTIAL DIAGNOSIS Waldenstro¨m’s macroglobulinemia should be regarded as a distinct clinicopathological entity and be confined to those patients with lymphoplasmacytoid lymphoma involving the bone marrow who have demonstrable serum IgM monoclonal protein. This diagnosis is supported by immunophenotypic studies by flow cytometry and/or immunohistochemistry. The diagnosis of WM can be made irrespective of IgM concentration provided that there is evidence of lymphoplasmacytoid infiltration of the bone marrow.53 Most patients with the diagnosis of WM have symptoms, signs or complications attributable to tumor infiltration and/or monoclonal IgM. Such patients are classified as symptomatic WM. Nevertheless, some patients who fulfill the diagnostic criteria of WM are being diagnosed by chance without any symptoms or signs. These patients should be classified as asymptomatic or smouldering WM and should not be treated at diagnosis because they may remain stable for many years. Some studies have indicated that prognostic factors for early progression were mild anemia, higher levels of IgM and elevated serum b2-microglobulin.54

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It is also well recognized that in some patients with clinically overt manifestations due to the biological effects of the monoclonal IgM, there is no evidence of bonemarrow infiltration by lymphoplasmatoid lymphoma. Such patients usually have peripheral neuropathy, cryoglobulins, cold agglutinin disease, AL amyloidosis, or any of the other rare clinical manifestations. It is appropriate to consider these patients as having an IgM-related disorder. These patients need treatment to reverse complications from the monoclonal IgM despite absence of overt lymphomatous involvement.23,53 Patients with asymptomatic monoclonal IgM without morphologic evidence of bonemarrow infiltration can be classified as having IgM-MGUS. This condition is by far the most common among individuals with a monoclonal IgM. Some patients may have detectable bone-marrow clonal B cells by flow cytometry but without morphological evidence of bone-marrow infiltration at trephine biopsy. These patients should be classified as IgM-MGUS until further outcome data become available.55 A monoclonal IgM may be present in virtually all subtypes of peripheral B-cell disorders, and although monoclonal protein concentrations are generally higher in WM there is considerable overlap. In such cases immunophenotypic criteria may be helpful for an accurate diagnosis.56 INDICATIONS FOR TREATMENT Initiation of therapy is indicated for patients who present or develop symptoms and signs due to malignant infiltration of organs and tissues, due to circulating IgM and due to deposition of IgM in various tissues (Table 3).57 Initiation of therapy should not be based on serum monoclonal protein levels per se, since these may not correlate with clinical manifestations of WM. However, a serum monoclonal protein level O50 g/L places patients at higher risk for hyperviscosity and requires a thorough history and physical examination for evidence of pertinent symptoms and signs.

RESPONSE CRITERIA During the Second International Workshop on WM a consensus panel proposed guidelines for standardized response criteria that are summarized below.58 Table 3. Indications for initiation of treatment in WM. B symptoms (fever, night sweats, weight loss) Bulky lymphadenopathy Symptomatic organomegaly Symptoms and signs of hyperviscosity Symptomatic cryoglobulinemia Symptomatic peripheral neuropathy Cold-agglutinin anemia Immune hemolytic anemia and/or thrombocytopenia Hemoglobin !10 g/dL Platelet count !100!109/L Amyloidosis Evidence of disease transformation

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Complete response (CR) This requires the complete disappearance of serum and urine monoclonal protein by immunofixation, resolution of lymphadenopathy and of organomegaly, and no signs or symptoms that are directly attributable to WM. These findings must be confirmed 6 weeks later. Absence of malignant cells by bone-marrow histologic evaluation is required. Partial response (PR) This is defined by a reduction of R50% in serum monoclonal protein concentration on electrophoresis and a reduction of R50% in lymphadenopathy and in organomegaly on physical examination or computed tomography. Symptoms and signs that are directly attributable to WM must resolve. Relapse from CR This is the reappearance of serum monoclonal protein as determined by immunofixation confirmed by a second measurement or reappearance of clinically significant symptoms and signs attributable to WM or development of any other clinically significant disease-related complication. Progressive disease (PD) Progressive disease is defined by an increase of O25% in serum monoclonal protein levels from the lowest attained response value as determined by serum electophoresis, confirmed by another measurement 3 weeks later. Progressive disease may also be documented if there is worsening of anemia, thrombocytopenia, leukopenia, lymphocytosis, lymphadenopathy or organomegaly directly attributable to WM or appearance of disease-related complications such as unexplained fever, night sweats, weight loss, neuropathy, nephropathy, symptomatic cryoglobulinemia or amyloidosis.

TREATMENT Chemotherapy Alkylating agents The standard primary therapy for patients with WM has been the administration of oral alkylating agents such as chlorambucil, melphalan or cyclophosphamide. The agent most commonly used has been oral chlorambucil. Approximately 50% of patients achieve a partial response; complete responses are rare, and several months are required to determine the chemosensitivity of the disease. Chlorambucil has been administered either on a daily basis at low doses or intermittently at higher doses. A recently reported randomized trial showed a similar median survival of 5.4 years with either schedule.59 The optimal duration of chlorambucil administration has not been prospectively defined. There is no evidence that maintenance therapy prolongs the survival of

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patients with WM. Prolonged exposure to alkylating agent treatment increases the likelihood of myelodysplasia and secondary leukemia.23 Nucleoside analogues Fludarabine and 2-chlorodeoxyadenosine (cladribine) are purine nucleoside analogues which have been effective for many patients with a variety of low-grade lymphoid malignancies. A preliminary European multicenter trial included 20 previously untreated patients who received fludarabine 25 mg/m2 intravenously daily for 5 consecutive days every 4 weeks. Objective responses occurred in 79% of patients and the median time to progression was 40 months.60 The largest fludarabine trial was performed by SWOG and included 118 previously untreated symptomatic patients. At least 50% reduction of serum monoclonal protein levels was documented in 40% of patients, including complete responses in 3%. The median time to response was 83 days (range 23–676 days). The median event-free and overall survival were 43 months and 84 months, respectively.61 The published experience of single-agent cladribine in previously untreated patients is more restricted, with less than 100 patients treated in several small phase II studies. Continuous intravenous infusion for 7 days, 2 h intravenous infusion daily for 5 days or subcutaneous injection of the drug have been used. Objective responses have been documented in 64-90% of patients.62–66 The number of cycles administered in these studies varied considerably, but good responses have been documented when patients were restricted to a maximum of two cycles of cladribine. The median time to a 50% reduction of monoclonal protein was 1.2 months and the median progression-free survival was 18 months in one study.62 However, other studies have reported longer times to response (median 5.8 months).66 Both fludarabine and cladribine have been administered to patients failing primary treatment with alkylating agents. More experience has been accumulated with fludarabine. Approximately a third of patients respond to fludarabine.67,68 The activity of this agent has been confirmed in a randomized trial.69 Cladribine is also active in previously treated patients with WM. Responses have been documented in approximately 40% of patients.64–66,70–72 Treatment with a nucleoside analogue is more effective in patients who do not respond to primary treatment with alkylating agents, especially when treated within the first year. Combination chemotherapy Combinations of alkylating agents—with or without a vinca alkaloid or a nitrosourea or an anthracycline—have been used as primary treatment of WM. These regimens include the M2 protocol (melphalan, cyclophosphamide, carmustine, vincristine and prednisone), COP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicine, vincristine and prednisone) and CMP (cyclophosphamide, melphalan and prednisone).23,73,74 Although no prospective randomized trials have compared those regimens to standard chlorambucil, there is no evidence of benefit from these combinations. In a limited number of studies, alkylating agents have been added to nucleoside analogues. Two cycles of oral cyclophosphamide and subcutaneous cladribine has been administered to 37 patients with previously untreated patients with WM. At least a partial response was documented in 84% of patients, and the median duration of response was 36 months.75 Fludarabine has been combined with

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intravenous cyclophosphamide with a 55% response rate in 11 symptomatic patients with mainly primary refractory disease or relapse on treatment.76 High-dose therapy The published experience with high-dose therapy supported by autologous stem-cell transplantation (ASCT) in WM is relatively limited and is primarily based on retrospective studies.77–79 Patients received ASCT during various phases of their disease, usually several years after their original diagnosis, and most were heavily pretreated. Some patients received high-dose chemotherapy alone, such as with melphalan, whereas others were treated with total body irradiation combined with melphalan, cyclophosphamide or etoposide. The median age of these patients was around 55 years, i.e. several years younger than the average patient with WM. Highdose therapy was well tolerated, with a treatment-related mortality of !5%. This modality induced objective responses in almost all patients, even in patients who were clearly refractory to several regimens of standard chemotherapy. Since the series contained a small number of patients treated at various phases of their disease, it is not possible to assess the duration of response after ASCT. However, some patients surviving without progression for at least 5 years have been reported. These data have indicated that ASCT in WM is feasible, safe, and associated with significant cytoreduction. In view of the prolonged survival of most patients with WM, prospective studies with a larger number of patients are needed to define the role of ASCT, focusing primarily in patients with poor prognostic features at diagnosis. It should be also mentioned that prior exposure to nucleoside analogues may impair stem-cell collection. Thus patients who are candidates for high-dose therapy should proceed to stem-cell collection before initiation of treatment with nucleoside analogues. Very limited results have been reported with the use of allogeneic transplantation in WM. High CR rates have been reported, but the treatment-related mortality is 40%.78,79 Allogeneic transplantation should be considered only in young patients with far advanced, refractory disease for whom no other options are available. Monoclonal antibody therapy Rituximab is a chimeric human/mouse monoclonal antibody that binds avidly to the CD20 antigen which is expressed on 95% of B-cell lymphoma cells. Since CD20 is almost always present on WM cells, rituximab became a rational treatment for this disease. Several retrospective and prospective studies have indicated that rituximab may induce objective responses in approximately 30–40% of previously treated patients.80–84 There is preliminary experience with rituximab in previously untreated patients with WM. One third achieved an objective response, and the median time to progression was 13 months.84,86 Rituximab is a well-tolerated treatment. Because myelosuppression is negligible, rituximab may represent the treatment of choice for patients who present with or develop cytopenias and for patients who are candidates for stem-cell collection and high-dose therapy. Time to response after rituximab is slow and exceeds 3 months on the average. Patients with baseline serum monoclonal protein of %40 g/L IgM are more likely to respond.83,85 In many patients, a transient increase of serum IgM may be noted immediately following initiation of treatment. Such an increase does not herald

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treatment failure, and most patients will return to their baseline serum IgM level by 12 weeks.83,87 However, patients with elevated baseline serum IgM levels may be particularly at risk for a hyperviscosity-related event, and in such patients plasmapheresis should be considered in advance of rituximab therapy. Because of the decreased likelihood of a response in patients with higher IgM levels, as well as the possibility that serum IgM and viscosity levels may abruptly rise, rituximab monotherapy should not be used for the treatment of patients at risk for hyperviscosity symptoms. Because rituximab is an active and a non-myelosuppressive agent, its combination with chemotherapy has a sound rationale. Weber et al administered the combination of rituximab, cladribine and cyclophosphamide to 17 previously untreated patients with WM. At least a partial response was documented in 94% of patients, including a complete response in 18%. With a median follow-up of 21 months no patient has relapsed.75 Treon et al administered a combination of rituximab and fludarabine to 14 patients, including some previously untreated patients. An objective response was noted in 75% of patients, with response duration ranging from 3 to 11C months.88 Interferon-a Interferon-a (IFN-a) has been evaluated in a limited number of patients with WM. Partial responses have been reported in approximately one third of patients.89,90 Thalidomide Because thalidomide is active in multiple myeloma, this agent has been administered to patients with WM. In the initial phase II study of single-agent thalidomide, five (25%) of 20 patients achieved a partial response. The time to response was short, ranging between 0.8 and 2.8 months, and the median duration of response was 11 months. Due to several side-effects, most patients could not tolerate more than 400 mg of thalidomide daily.91 Two subsequent studies assessed the activity of the combination of clarithromycin, low-dose thalidomide and dexamethasone in patients with WM. Partial response rate was 83 and 25%, respectively.91,92 From this limited experience it appears that thalidomide—with or without clarithromycin and dexamethasone—may be of benefit for some patients with WM. This treatment could be considered for previously treated patients with prominent cytopenias who have failed treatment with other more active regimens. Plasmapheresis In some patients with WM the predominant symptoms are due to elevated serum viscosity. Because 80% of IgM is intravascular, plasmapheresis—conducted with a continuous blood flow separator with albumin and saline replacement—can rapidly reduce the amount of circulating IgM. Relatively small reductions in serum IgM (20– 30%) can dramatically reduce viscosity (50–60%) with resolution of symptoms.94 Concomitant initiation of systemic therapy is usually indicated in order to reduce the monoclonal protein synthesis. However, some patients with predominant symptoms of hyperviscosity have been effectively managed for several years with plasmapheresis alone. This strategy may be considered in patients who fail systemic treatment. Intensive plasmapheresis has also been used successfully in patients with IgM-induced complications such as cryoglobulinemia, cold agglutinin disease and peripheral neuropathy.95

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Table 4. Adverse prognostic factors in WM. Advanced age Impaired performance status B symptoms Organomegaly Lymphadenopathy Hyperviscosity Cryoglobulinemia Diffuse bone-marrow infiltration Anemia Leucopenia Thrombocytopenia Hypoalbuminemia Elevated serum b2-microglobulin levels

Splenectomy A small number of chemotherapy-resistant patients with WM have been described in whom a major decrease in monoclonal protein concentration occurred after splenectomy alone. Some of these remissions lasted for many years.93 The removal of a major source of IgM-producing cells and elimination of hypersplenism may explain in part the beneficial effect of splenectomy. With currently available data it is not possible to predict how often splenectomy may be helpful, and the possible role of this procedure requires further evaluation.

PROGNOSIS The median survival of patients with WM ranges between 5 and 10 years in different series. This discrepancy probably reflects different inclusion criteria. Several studies have evaluated the impact of several clinical and laboratory variables on patient outcome (Table 4).96–100 Age is an important prognostic factor for survival. Anemia, which reflects both marrow infiltration and the serum level of monoclonal protein, is a strong predictor of survival in all published series. Leucopenia and thrombocytopenia are identified as significant survival predictors in most studies. Serum albumin levels were correlated with survival in two large WM populations by multivariate analysis.13,18 High b2-microglobulin values were linked to poor survival in all of the studies in which they were analysed.14,17,18 At present, insufficient data exist to affirm the use of any prognostic marker in the initiation and selection of therapy. Studies which prospectively apply prognostic markers in WM are needed.

SUMMARY WM is a distinct clinicopathological entity that should be confined to patients with lymphoplasmacytoid lymphoma who have serum monoclonal IgM. Immunophenotypic analysis supports the concept that the cell of origin of WM is a mature IgMC B

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lymphocyte that has exited the germinal center. The only recurrent abnormality in WM is deletion of the long arm of chromosome 6, and further studies are needed to elucidate its role in the pathogenesis of WM. Asymptomatic patients should not be treated. There are clearly defined indications which may help physicians to decide whether a patient needs treatment or not. The primary treatment of symptomatic patients could be either chlorambucil or a nucleoside analogue (fludarabine or cladribine) or rituximab. There are no prospective randomized trials to support the selection of one agent over another. High-dose therapy with autologous stem-cell transplantation is effective in patients whose disease has become resistant to multiple conventional treatments. Prospective studies are needed to identify at diagnosis patients with WM who are more likely to benefit from early administration of high-dose therapy. Most studies have indicated that advanced age, anemia and elevated b2microglobulin are adverse prognostic factors. Practice points † Waldenstro¨m’s macroglobulinemia is a distinct clinicopathological entity characterized by the presence of lymphoplasmacytoid lymphoma involving the bone marrow and by the detection of serum monoclonal IgM † there are data to support the idea that WM may originate from a postgerminal-center memory B lymphocyte † the clinical and laboratory manifestations of WM are related to direct tumor infiltration and to the amount and specific properties of monoclonal IgM † asymptomatic patients should not be treated. There are clear indications for initiation of treatment. Initiation of treatment should not be based solely on IgM levels † alkylating agents, nucleoside analogues and rituximab are reasonable choices for primary treatment of WM † high-dose therapy with autologous stem-cell transplantation should be considered for patients who have developed resistance to conventional treatment † advanced patient age, anemia, and elevated serum b2-microglobulin may predict impaired survival

Research agenda † further studies are needed to assess whether deletion of the long arm of chromosome 6 may have a pathogenetic role in WM † gene array profiling may provide further insight in the pathogenesis and propagation of WM † prospective randomized trials are required to clearly define the optimal primary treatment of WM † combinations that include all three classes of active agents are worthy of study † early application of high-dose therapy with autologous stem-cell transplantation needs to be studied in patients who present with adverse prognostic features

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ACKNOWLEDGEMENTS We are grateful to Constantina Kakoyiannis and to Asimina Petropoulou for editing and typing the manuscript.

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