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Lymphoplasmacytic lymphoma – Waldenstrom’s magroglobulinemia

1. DEFINITION

Immunocytoma is an old-fashioned term used to describe a distinct entity with individual morphologic, immunophenotypic and clinical features that includes cases formerly recognized as immunocytoma, lymphoplasmacytic type in the Kiel classification ( Banks 1992; Lennert 1978). Immunocytoma was not included in the Working Formulation; it mostly corresponds to small lymphocytic lymphoma; plasmacytoid, diffuse mixed small and large cell according to that classification. The terms lymphoplasmacytoid lymphoma, plasmacytoid lymphocytic lymphoma and immunocytoma do not appear to define a single entity. B-cell neoplasms may show maturation to plasmacytoid or plasma cells containing CIg, including B-chronic lymphocytic leukaemia, mantle-cell, follicular, and marginal-zone lymphomas. These cases should be classified according to their major features, and not as lymphoplasmacytoid lymphomas (Harris 1994). In contrast, the terms immunocytoma or lymphoplasmacytoid lymphoma should be reserved to a distinct neoplasm of small lymphoid cells that show maturation to plasma cells, with CD5- phenotype and without features of other lymphoma types. It corresponds to most cases of Waldenström macroglobulinaemia (WM). WM was originally described in 1944 by Jan G. Waldenström who reported two patients with oronasal bleeding, anaemia, lymphadenopathy, hypergammaglobulinaemia, an elevated sedimentation rate, hyperviscosity, normal bone films, cytopenias, and a bone marrow with a predominantly lymphoid infiltrate ( Waldenstrom 1944). This lymphoma has been postulated as arising from a CD5- peripheral B lymphocyte stimulated to differentiate to a plasma cell. The presence of IgM paraproteinemia in low-grade lymphomas is usually considered a clinical syndrome, and it is known as WM. WM has been diagnosed in patients with low-grade B-cell lymphomas that were classified using a variety of terms: well-differentiated lymphocytic, plasmacytoid (Rappaport); plasmacytic-lymphocytic (Lukes-Collins); immunocytoma, lymphoplasmacytic type (Kiel); small lymphocytic, plasmacytoid (Working formulation); lymphoplasmacytoid lymphoma (immunocytoma) (Revised European American Lymphoma – REAL); lymphoplasmacytic lymphoma/Waldnestrom’s macroglobulinemia (World Health Organization – WHO). WM is a distinct B-cell lymphoproliferative disorder characterized primarily by the infiltration of lymphoplasmacytic cells into bone marrow and the demonstration of IgM monoclonal gammopathy. This condition is considered to be lymphoplasmacytic lymphoma (LPL), as defined by the REAL and WHO classification systems ( Harris 1994). LPL/WM is characterized by a monoclonal expansion of predominantly small B-lymphocytes with variable plamacytoid differentiation; small B-lymphocytes are usually CD5-, CD10- and CD23- and they are associated with serum IgM paraprotein (Lin 2005).

2. INCIDENCE AND RISK FACTORS

Usually, Ig heavy and light chain genes are rearranged. Most patients have a normal karyotype, but abnormalities were described. The t(9;14)(p13;q32) is present in near 50% of cases of LPL. This chromosomal translocation involves a junction between 9p13 and the switch micro region of the Ig heavy chain locus on 14q32 (Iida 1996). The 9p13 breakpoint contains the PAX-5 gene which encodes a B-cell specific transcription factor involved in the control of B-cell proliferation and differentiation. The translocation causes the juxtaposition of the PAX-5 gene to the IgH locus in the opposite direction of transcription, resulting in an 11-fold overexpression of PAX-5 mRNA and a significantly reduced expression of the p53 gene, which is normally regulated by PAX- 5. PAX-5 gene is the target of the t(9;14) in LPL whereby its expression may be deregulated by juxtaposition to IgH regulatory elements, thus contributing to lymphomagenesis ( Iida 1996). These results are not universally recognised; some authors suggest that deletion of 6q is the most common finding in LPL/WM, with 6q21 deletion observed in 42% of patients by interphase FISH. However, deletion of 6q is not a specific feature of LPL/WM (‘voce_bibliografica.jsp?Id=8838’)”>Lin 2005; Schop 2002).

3. PATHOLOGY AND BIOLOGY

3.1 Morphology

LPL occurs in older adults (median age 65, range 27-82), involving bone marrow, lymph nodes and spleen, while extranodal involvement and leukemic phase are rare. A monoclonal serum paraprotein of IgM type and hyperviscosity symptoms may occur in more than 20% of cases (WM) (Papamichael 1999; Zukerberg 1993 ). Clinical presentation usually consists of disseminated disease, less than 10% of patients have localized lymphoma (stages I-IIE). WM is more common among males (62%) with a median age of 65 years, only 1% of patients are younger than 40 years. Most patients with the diagnosis of WM have symptoms attributable to tumour infiltration (cytopenia, fever, night sweats, weight loss, lymphadenopathy, organomegaly) and/or monoclonal protein (hyperviscosity, cryoglobulinemia, cold agglutinin, neuropathy, amyloidosis); however, some patients are asymptomatic (Dimopoulos 2005). Weakness, fatigue and bleeding are common presenting symptoms. Blurred or impaired vision, dyspnea, loss of weight, neurologic symptoms, recurrent infections, and congestive heart failure may occur. Bone pain is rare. Physical findings include pallor, hepatosplenomegaly and lymphadenopathy. Retinal lesions include haemorrhages, exudates and venous congestion. Abnormalities in platelet adhesiveness, prothrombin time, and thromboplastin generation play a role in the pathogenesis of the bleeding tendency. Thrombocytopenia from the anti-platelet activity of monoclonal IgM has been reported ( Varticovski 1987). Other signs consistent with WM are sudden deafness, spinal muscular atrophy, multifocal leukoencephalopathy, peripheral neuropathy, renal failure, and pleural effusion. In fact, 3 to 5% of patients with WM have lung involvement, such as diffuse pulmonary infiltrates, nodules, massese or pleural effusion. Renal failure is due to infiltration of the kidney interstitium by lymphoplasmacytoid cells, with renal and perirenal masses. Malignant infiltration of the stomach and the bowel has been reported. Patients with WM can also present infiltration of the dermis, like as maculopapular lesions, plaques or nodules, and orbital involvement caused by lesions involving the retro-orbital lymphoid tissue and lachrymal glands and often associated with infiltration of the conjunctiva and vitreitis. Thirty percent of patients with WM has a serum viscosity of > 4 centipoises (normal ¡Ü 1.8), unexpectedly one third of these patients had not symptoms (Axelsson 1986 ). In effect, the relationship between serum viscosity and clinical manifestations is not precise. Hyperviscosity syndrome due to an increase of the whole blood viscosity, most commonly manifested by bleeding, is also associated to blurring or loss of vision, dizziness, headache, vertigo, nystagmus, hearing loss, ataxia, paresthesias, diplopia, somnolence, and come. Malignant infiltration of CNS is rare in WM patients. Bing and Neel described two patients with CNS involvement from infiltration of plasma cells and lymphocytes that in retrospect was WM {Bing, 1936 243 /id}. This syndrome (Bing-Neel syndrome) can be divided into a tumoral (intraparenchymal) and infiltrative form and consists of confusion, memory loss, disorientation, motor dysfunction and coma. The clinical characteristics of the infiltrative form are similar to neoplastic meningitis. A few cases of ocular motor cranial neuropathy due to elevated intracranial pressure or direct infiltration of the sixth nerves by the malignant cells of WM have been reported ( Bhatti 2005). Patients with WM have moderate to intense normochromic normocytic anemia, increased plasmatic volume with a relative reduction of hematocrit, greatly increased erythrocyte sedimentation rate, lymphocytosis, hypocholesterolemia, and hyperuricemia. A tall, narrow peak, or dense band characterizes the serum protein electrophoretic pattern of Waldenstrom’s macroglobulinemia, almost always of gamma-mobility. This pattern is indistinguishable from that of multiple myeloma. Of the IgM proteins, 75% have a x-light chain. IgG and IgA levels are frequently reduced. Low-molecular-weight IgM (7S) is present and may account for a large part of the elevated IgM. A monoclonal light chain protein is present in the urine of 80% of cases.

3.2 Immunophenotype

The analysis in flow cytometry immunophenotyping shows that cells of LPL/WM are B cells positive for monocytic Ig light chains, IgM, pan-B-cell markers such as CD19 and CD20, and negative for CD3 and CD103; CD11c, CD25 and CD22 are expressed respectively in 81%, 71% and 33% of cases. The plasma cells in LPL/WM are monotypic, positive for cytoplasmic Ig. In the WHO classification, the cells of LPL/WM are usually negative for CD5, CD10 and CD23 ( Lin 2005). In one study of Remstein, only 58% of patients has the typical immunophenotype as described by the WHO classification and variable expression of CD5, CD10 and CD23 is observed (Remstein 2003). Additionally, at immunophenotypic study, WM cells are CD25+, CD27+, CD75-, CD79+, CD138-, FMC7+, Bcl2+, Bcl6-, PAX5+, (Owen 2001; Owen 2005; San 2003). The expression at the immunophenotype of all antigens sIgM+ CD5- CD10- CD19+ CD20+ CD23-, in association with a non-paratrabecular pattern of infiltration at bone marrow, is diagnostic of WM (Owen 2001; Owen 2005).

3.3 Genetic features

Usually, Ig heavy and light chain genes are rearranged. Most patients have a normal karyotype, but abnormalities were described. The t(9;14)(p13;q32) is present in near 50% of cases of LPL. This chromosomal translocation involves a junction between 9p13 and the switch micro region of the Ig heavy chain locus on 14q32 ( Iida 1996). The 9p13 breakpoint contains the PAX-5 gene which encodes a B-cell specific transcription factor involved in the control of B-cell proliferation and differentiation. The translocation causes the juxtaposition of the PAX-5 gene to the IgH locus in the opposite direction of transcription, resulting in an 11-fold overexpression of PAX-5 mRNA and a significantly reduced expression of the p53 gene, which is normally regulated by PAX- 5. PAX-5 gene is the target of the t(9;14) in LPL whereby its expression may be deregulated by juxtaposition to IgH regulatory elements, thus contributing to lymphomagenesis (Iida 1996). These results are not universally recognised; some authors suggest that deletion of 6q is the most common finding in LPL/WM, with 6q21 deletion observed in 42% of patients by interphase FISH. However, deletion of 6q is not a specific feature of LPL/WM (Lin 2005; Schop 2002) and it is not known to have clinical associations, but a recent study ( Ocio 2007) suggested that patients tend to have more aggressive disease and shorter survival.

3.4 Genomics and proteomics

Use of gene expression arrays as markers for genomic abnormalities and as tools for disease profiling is useful to characterize genomic changes responsible for pathogenesis in WM. Conversely to those reported for multiple myeloma, the genetics of WM seem to be simpler, with less observed aneuploidy and the only abnormalities thus far identified being 6q deletions. Gene expression profiling (GEP) has been employed to compare WM with other hematologic malignancies as a means to identify a gene expression signature and consequences of gene dysregulation associated with WM (Chng 2006). Genetic variations of WM were found to cluster with chronic lymphocytic leukemia and normal B cells following unsupervised hierarchic clustering. Only a small set of genes, including the gene encoding interleukin-6 and genes in the mitogen-activated protein kinase pathway, was found to be specific for WM ( Chng 2006). WM cells were recently separated into those with B-cell and plasma cell morphology for gene expression comparison with chronic lymphocytic leukemia, multiple myeloma, and normal individuals (Gutierrez 2007). Following unsupervised hierarchic clustering, WM B-cell samples clustered with chronic lymphocytic leukemia whereas WM plasma cell samples segregated with multiple myeloma. B cells and plasma cells from WM patients exhibit different patterns of gene expression compared with B cells and plasma cells from patients with chronic lymphocytic leukemia and multiple myeloma (Gutierrez 2007). The genetic abnormalities associated with specific cell subpopulations ultimately influence the proteome and the potential for therapeutic targeting. In fact, in that study, interleukin-6 a molecule currently being considered as a possible therapeutic target, was found upregulated in WM samples, which could explain the clinical observation of elevated serum levels of C-reactive protein in many WM patients. Interleukin-6 may be one of the many possible factors explaining anemia in these patients. Proteomic analysis of signaling pathways performed in samples from patients with WM obtained before and after treatment with a proteasome inhibitor showed several overlaps with multiple myeloma, suggesting similar pathways being utilized in cell signaling for B-cell differentiation ( Mitsiades 2003). However, some groups of proteins expressed by either WM or multiple myeloma but not both were distinguished, indicating some differences in cellular response induced by proteasome inhibitor treatment.

3.5 Differential diagnoses

Differential diagnosis between WM and other B-cell lymphoproliferative (mantle cell lymphoma, B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma, follicular lymphoma, multiple myeloma and, in particular, marginal zone lymphoma) and plasma cell disorders can be problematic due to the lack of morphological, immunophenotypic and genetic features specific to WM. Differential diagnosis with marginal zone lymphoma is especially difficult. Conversely to the classical presentation of WM (see below), marginal zone lymphoma exhibit a more common involvement of gastrointestinal tract in the extranodal form (MALT-type lymphoma), with peripheral lymphadenopathies in the nodal form, or prominent splenomegaly, marrow infiltration, monoclonal gammopathy, and peripheral villous lymphocytes in the splenic form of MZL. Among genetic features, MZL are variably associated with t(11;18) and trisomy 3, while IgH translocations are non-specific and rare in WM. The most common differential diagnosis of WM is IgM MGUS. The diagnostic criteria for WM established at the Second International Workshop on WM have been updated to take into account the data indicating that making distinctions among IgM MGUS, smouldering WM and WM are clinically and prognostically relevant ( Rajkumar 2006). Patients with IgM MGUS (<10% marrow infiltration and <30 g/l of serum monoclonal IgM) have a risk of progression to symptomatic disease of only approximately 1.5% per year (Kyle 2003), with a reduced mortality ratio (Gobbi 2005). Asymptomatic WM had a mortality rate comparable to that of the general population, while symptomatic WM had a mortality rate greater than five times the general population (Gobbi 2005). Thus, it is important to differentiate symptoms and clinical relevance of these disorders based on their underlying causes: those related to the clonal proliferation/tumour infiltration of the bone marrow and other lymphoid organs, and those secondary to the rheological effects of the monoclonal protein (Gertz 2000). Consequently, the establishment whether the IgM MGUS is concurrent with a malignant process and/or if it is problematic in and of itself, given its potential properties as an autoantibody or its possible amyloidogenicity, are essential questions in the management of patients with known or suspected IgM MGUS ( Fonseca 2007). Importantly, patients with an IgM MGUS with clinical manifestations related to circulating or tissue deposition of IgM, not meeting the criteria for WM (IgM-related disorder), may also require treatment. Symptoms and signs suggestive of an associated WM with high tumour bulk include constitutional and hyperviscosity symptoms, adenopathy or organomegaly. Cytopenias, particularly anaemia, may also develop from significant marrow infiltration, but also may be a consequence of autoimmune haemolysis, drug therapy or high IL-6 levels. Thrombocytopenia can result from tumour, therapy, immune thrombocytopenic purpura or splenomegaly.

4. CLINICAL FEATURES

4.1 Presentation

Complete staging work-up for LPL is the same that routinely used for other NHL. It includes an accurate physical examination, complete hematological and biochemical exams, total-body computerized tomography, and bone marrow aspirate and biopsy. Additional investigations are recommended for patients with a new diagnosis of WM: plasma viscosity, renal and hepatic function, direct antiglobulin test and cold agglutinin titre if positive, cryoglobulins and beta-2-microglobulin. Patients with peripheral neuropathy should have nerve conduction studies and anti-myelin-associated glycoprotein (MAG) serology ( Johnson 2006). The Ann Arbor staging system developed for use in Hodgkin’s disease is not applicable to LPL. Moreover, stage definition is irrelevant in WM considering that initiation of therapy is decided on the bases of prognostic factors (see below) and the development of disease-related symptoms and signs (Kyle 2003; Dimopoulos 2005). No reliable molecular markers are available for monitoring of minimal residual disease in LPL.

4.1.1 Hematological features and complications

Initial laboratory signs most commonly consist of the detection of a monoclonal IgM and varying degrees of normochromic normocytic anaemia (Facon 1993; Garcia-Sanz 2001). The anaemia is probably multifactorial and may be due to the expansion of clonal cells in the bone marrow, increased plasma volume, reduced erythropoietin production due to hyperviscosity and may elevated levels of IL-6 ( Singh 1993). Anaemia may also be secondary to previous treatment. Erythropoietin containing products have been used successfully in patients, but this strategy could exacerbates or induces hyperviscosity. Abnormalities in platelet adhesiveness, prothrombin time, and thromboplastin generation play a role in the pathogenesis of the bleeding tendency. Thrombocytopenia can be observed as a consequence of diffuse bone marrow infiltration (Facon 1993; Garcia-Sanz 2001), ITP, treatment-related toxicity, splenomegaly, or anti-platelet activity of monoclonal IgM (Varticovski 1987). Patients with WM have greatly increased erythrocyte sedimentation rate, hypocholesterolemia, and hyperuricemia. A tall, narrow peak, or dense band characterizes the serum protein electrophoretic pattern of WM, almost always of gamma-mobility. This pattern is indistinguishable from that of multiple myeloma. Of the IgM proteins, 75% have a ê-light chain. IgG and IgA levels are frequently reduced. Low-molecular-weight IgM (7S) is present and may account for a large part of the elevated IgM. A monoclonal light chain protein is present in the urine of 80% of cases.

4.1.2 Hyperviscosity

Hyperviscosity is a central feature in WM patients. The large size of the IgM molecule and other factors like the hydration state and the red cell mass make the peripheral blood more viscous, with a resulting slower transit time through capillaries (Gertz 1995). The relationship between serum viscosity and clinical manifestations is not precise, and a general absolute value for viscosity at which hyperviscosity becomes clinically relevant do not exist. Thirty percent of patients with WM has a serum viscosity of >4 centipoises (normal ¡Ü1.8), unexpectedly one third of these patients had not symptoms, but nearly all patients with a viscosity >8 are symptomatic (Axelsson 1986). Risk for hyperviscosity symptoms is high in patients with a serum monoclonal IgM of >50 g/l (Dimopoulos 2005). Hyperviscosity syndrome, most commonly manifested by bleeding (p.e., in noise, mouth, retina), is also associated to blurring or loss of vision, dizziness, headache, vertigo, nystagmus, hearing loss, ataxia, paresthesias, diplopia, somnolence, and come. Neurological deficits attributed to hyperviscosity are not specific and heterogeneous, ranging from confusion to dementia, and constitute a clinical indication for plasma exchange, even in cases without a clear cause-effect relation.

4.1.3 Neurological symptoms

Malignant infiltration of CNS is rare in WM patients. Bing and Neel described two patients with CNS involvement from infiltration of plasma cells and lymphocytes that in retrospect was WM (Bing 1936). This syndrome (Bing-Neel syndrome) can be divided into a tumoral (intraparenchymal) and infiltrative form and consists of confusion, memory loss, disorientation, motor dysfunction and coma. The clinical characteristics of the infiltrative form are similar to neoplastic meningitis. A few cases of ocular motor cranial neuropathy due to elevated intracranial pressure or direct infiltration of the sixth nerves by the malignant cells of WM have been reported (Bhatti 2005). Other neurological signs consistent with WM are spinal muscular atrophy and multifocal leukoencephalopathy. Retinal lesions include haemorrhages, exudates and venous congestion; symptoms are usually a direct consequence of hyperviscosity, and can be detected by direct ophthalmoscopic examination ( Barras 1980; Robinson 1992). Orbital involvement is caused by lesions involving the retro-orbital tissues and lachrymal glands and is often associated with infiltration of the conjunctiva and vitreitis.

4.1.4 Peripheral neuropathy

Peripheral neuropathy is present in near 20% of WM patients. This is usually a distal, symmetric, chronic, demyelinating neuropathy, sometimes associated with abnormalities of proprioception and ataxia (Dellagi 1983; Nobile-Orazio 1987). Neuropathy in WM seems to be related to the monoclonal IgM, which can acts as an anti-myelin autoantibody, mostly against myelin-associated glycoproteins (Vital 1985; Ropper 1998), but neuropathy due to amyloidosis, vitamin B12 deficiency and cryoglobulinaemia has been also reported.

4.1.5 Other organs

Tumor cells can infiltrate other organs and result in hepatomegaly (20% of cases), splenomegaly (15%) and lymphadenopathy (15–20%) (Facon 1993; Morel 2000; Dhodapkar 2001; Garcia-Sanz 2001; Leblond 2004; Ghobrial 2006). Liver involvement is usually not clinically relevant. Other signs consistent with WM are renal failure, and pleural effusion. Renal failure is due to infiltration of the kidney interstitium by lymphoplasmacytoid cells, with renal and perirenal masses, while 3 to 5% of patients with WM have lung involvement, such as diffuse pulmonary infiltrates, nodules, massese or pleural effusion. Malignant infiltration of the stomach and the bowel has been reported. Patients with WM can also present infiltration of the dermis, like as maculopapular lesions, plaques or nodules. Some WM patients can develop light-chain-associated amyloidosis ( Gertz 1993, Gertz 1999; Kyle 1987), with associated cardiomyopathy in 44% of cases, and higher incidences of pleural and pulmonary involvement (Gertz 1993, Gertz 1999). In the subgroup of patients with WM-associated amyloidosis, cardiac amyloidosis represents the most common cause of death (Gertz 2003).

4.2 Diagnostic procedures

Serum monoclonal protein detection by serum protein electrophoresis and bone marrow aspirate and biopsy are the key procedures for WM diagnosis, monitoring and response assessment. Serum protein electrophoresis with samples warming to 37°C is useful to avoid interference of cold agglutinins or cryoglobulins. Monoclonal protein at diagnosis should be characterized by immunofixation, which could be useful to monitor disease remission. Since its heterogeneous clinical presentation and variable risk of involvement of several organs, WM diagnosis and monitoring can request for an ample number of laboratory, radiologic, electrobiologic, and bioptic studies. Standard laboratory testing should include complete blood count, blood chemistries, liver function tests, albumin, lactate dehydrogenase, CRP, serum viscosity and â2-microglobulin. The clinical value of some exams like Bence-Jones proteinuria and 24-h proteinuria remains to be defined, but could play a role in some uncommon differential diagnoses. Serum free light chains determination could be used as a surrogate tumour marker in WM, but its significance is obscure. As above described, chromosome analysis by conventional cytogenetics and FISH may help to distinguish WM from other B-cell disorders.

4.3 Staging

Complete staging work-up for LPL is the same that routinely used for other NHL. It includes an accurate physical examination, complete hematological and biochemical exams, total-body computerized tomography, and bone marrow aspirate and biopsy. Additional investigations are recommended for patients with a new diagnosis of WM: plasma viscosity, renal and hepatic function, direct antiglobulin test and cold agglutinin titre if positive, cryoglobulins and beta-2-microglobulin. Patients with peripheral neuropathy should have nerve conduction studies and anti-myelin-associated glycoprotein (MAG) serology (Johnson 2006). The Ann Arbor staging system developed for use in Hodgkin’s disease is not applicable to LPL. Moreover, stage definition is irrelevant in WM considering that initiation of therapy is decided on the bases of prognostic factors (see below) and the development of disease-related symptoms and signs ( Dimopoulos 2005; Kyle 2003). No reliable molecular markers are available for monitoring of minimal residual disease in LPL.

5. PROGNOSIS

5.1 Natural history

LPL/WM is an indolent malignancy that is not usually curable with conventional treatments. Patients treated with single alkylating agents show an overall response rate of 70%, with 12% achieving a complete response (Papamichael 1999). Response criteria and therapeutic outcomes were updated during the Third International Workshop on WM (Table 1) (Kimby 2006). Patients with WM have an overall response rate of 75%. Response rates at first recurrence are 50%. The median survival of patients with LPL is 50 – 60 months, which is significantly worse than that for patients with chronic lymphocytic leukemia /small lymphocytic lymphoma ( Papamichael 1999). Patients with WM show a median survival similar to that for the rest of the patients with LPL. Transformation to large cell lymphoma may occur.

Table 1 Summary of updated response criteria from the 3rd International Workshop on WM
RESPONSE (abbreviation) CRITERIA
Complete Response (CR) Disappearance of monoclonal protein by immunofixation; no histologic evidence of bone marrow involvement, resolution of any adenopathy/organomegaly (confirmed by CT scan), or signs or symptoms attributable to WM. Reconfirmation of the CR status is required at least 6 weeks part with a second immunofixation
Partial Response (PR) At least 50% reduction of serum monoclonal IgM concentration on protein electrophoresis and at least 50% decrease in adenopathy/organomegaly on physical examinationor on CT scan. No new symptoms or signs of active disease
Minor Response (MR) Ar least 25% but less than 50% reduction of serum monoclonal IgM by protein electrophoresis . No new symptoms or signs of active disease
Stable Disease (SD) A less-than 25% reduction and less-than 25% increase of serum monoclonal IgM by electrophoresis without progression of adenopathy/organomegaly, cytopenias, or clinically significant symptoms due to disease and/or signs of WM
Progressive Disease (PD) At least 25% increase in serum monoclonal IgM byprotein electrophoresis confirmed by a second measurement of progression of clinically significant findings due to disease (i.e., anemia, thrombocytopenia, leukopenia, bulky adenopathy/organomegaly) or symptoms (unexplained recurrent fever of at least 38.4°C, drenching night sweats, at least 10% body weight loss, or hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis) attributable to WM

“This research was originally published in Blood. Treon SP, Gertz MA, Dimopoulos M, Anagnostopoulos A, Blade J, Branagan AR, et al. “Update on treatment recommendations from the Third InternationalWorkshop on Waldenstrom’s Macroglobulinemia”. Blood 2006;107:3442-3446. © The American Society of Hematology”

5.2 Prognostic factors

Discrepancies in survival among different studies on WM likely reflect variations in prognostic factors distribution. The main adverse prognostic factors in the longest series are older age (>60 years), the presence of B symptoms, anemia, low albumin serum levels ( 41 u/L) and high beta 2-microglobulin values (Johnson 2006; Dimopoulos 2005; Papamichael 1999). In particular, hemoglobin and beta 2-microglobulin levels at diagnosis are important prognostic markers in WM; anemia reflects both marrow infiltration and the serum level of monoclonal protein and was a strong predictor of survival in all published series. High beta 2-microglobulin values were linked to poor survival in all of the studies in which they were analyzed (Garcia-Sanz 2001; Dhodapkar 2003; Merlini 2003; Dimoupoulos 2004 ). Leukopenia and thrombocytopenia were identified as significant survival predictors in most studies. However, the precise levels of cytopenia with prognostic significance remain to be determined. In most studies, the paraprotein concentration had no prognostic value in WM patients; this result rules out the hypothesis of a relationship between the extent of bone marrow infiltration and paraprotein concentration. It has been shown that serum beta 2-microglobulin, serum thymidine kinase, Karnofsky performance status, and platelet count independently predict progression-free survival in patients with LPL particularly in early disease stages (Hallek 1996).

6. TREATMENT

6.1 Treatment of stage I-II lymphoplasmacytic lymphoma

Standard therapeutic option for patients with stage I-II LPL is matter of debate. In the majority of prospective trials, LPL cases have been treated and analyzed together with other indolent lymphomas, rendering unreliable any conclusion. However, there is sufficient evidence supporting involved-field irradiation is suitable for individual clinical use on a type 3 level of evidence ( Gospodarowicz 1984;Sutcliffe 1985). This strategy is associated with a very high response rate and a 12-yr disease-free survival of 53%. The addition of post-radiation chemotherapy has not been studied in a prospective randomized fashion. Furthermore, the length and type of chemotherapy employed has varied widely from study to study. In a small randomized trial of patients with indolent lymphomas, the comparison between patients treated with radiotherapy alone and those treated with radiotherapy followed by adjuvant chemotherapy showed a 5-yr relapse-free survival of 55% and 63%, respectively (Monfardini 1980). In spite of this improvement in relapse-free survival, a significant difference in overall survival has not been observed.

6.2 Treatment of stage III-IV lymphoplasmacytic lymphoma

As for other indolent lymphomas, “watch and wait” policy is the standard approach to LPL in patients without systemic symptoms, vital organ embarrassment, bulky lesions, evident progression or transformation ( Portlock 1982). Delay of treatment until significant clinical progression does not seem to hamper the prognosis or subsequent response to treatment. The long natural history of this disease and that patients are often elderly with coexisting medical problems makes this approach attractive in many situations. Moreover, asymptomatic patients would certainly have a better quality of life without therapy. Withholding initial therapy theoretically limits exposure to chemotherapeutic agents and, it is hoped, prevents resistance at a time when those drugs are truly needed. The “watch and wait” policy has several potential disadvantages, however. Patients must be monitored closely to prevent insidious complications; systemic progression, bulky disease and systemic symptoms may make treatment more difficult; and it should be taken into account that many patients do not accept the option of letting their disease progress without therapy. With “watch and wait” strategy, overall survival is longer than 5 years, with a 10-yr survival of 70-75%, with spontaneous remissions in up to 23% of cases ( O’Brien 1991). Treatment for patients with stage III-IV LPL and systemic symptoms, vital organ embarrassment, bulky lesions, and/or evident progression is mandatory. A univocal standard therapeutic option for these patients does not exist. In these patients, other than age, performance status and other prognostic factors, therapeutic decision is conditioned by the criterion of therapeutic success. Oral monochemotherapy with alkylating agents is suitable for individual clinical use on a type 3 level of evidence in patients for whom overall survival is not the success criterion (Jones 1972). This strategy is particularly useful in aged patients with small tumor burden or very indolent disease. In these cases, monochemotherapy with chlorambucil or cyclophosphamide produces a 30% of complete remissions, with an overall response rate of 50-80% (Cadman 1982;Hoppe 1981; Jones 1972). The addition of corticosteroids makes no apparent difference. In spite of a higher response rate ( Canellos 1978; Hoppe 1981), CVP combination regimen (cyclophosphamide, vincristine and prednisone) shows equivalent efficacy to monochemotherapy.

6.3 Frontline treatment of Waldenstrom’s macroglobulinemia

In October 2004, during the Third International Workshop on WM, a consensus panel charged with providing treatment recommendations for WM, updated its recommendations on both frontline and salvage therapies. The panel analyzed ongoing clinical trials and conventional therapies. The regimens for the first-line of WM are single-agent therapy with alkylating agents, nucleoside analogs and the monoclonal antibody rituximab. The choice of first-line therapy must be done considering the presence of cytopenia, age and candidacy of autologous transplantation therapy. In fact, for patients who may be eligible for autologous transplantation, a therapy with alkylating agents and nucleoside analogs should be limited because of their depletion of stem cells. The panel also considered therapeutic options for relapsed disease ( Treon 2006).

“Watch and wait” policy is the standard approach to WM in patients without anemia, systemic symptoms, significant hepatosplenomegaly, bulky lesions, or hyperviscosity. The standard option for patients with symptomatic or progressive disease has not been yet established. However, chlorambucil, in an initial dose of 6-8 mg/day, is suitable for individual clinical use on a type 3 level of evidence. A combination of chlorambucil and prednisone for 1 week every 4-6 weeks is also efficacious. The response rate is 60% and the median survival approximately 60 months (Garcia-Sanz 2001). The use of combination chemotherapy including alkylating agents and vinca alkaloids is associated with an 80% response rate (Ngan 2003). Several additional drugs, like interferon (Rossi 1991), fludarabine and 2-chlorodeaoxyadenosine have been reported as efficacious in WM. Treatment with fludarabine in first line is associated with a response rate from 38% to 100% ( Tamburini 2005) and with cladribrine with a response rate of 55% to 100%. The median duration of response to purine analogues ranges from 13 to 41 months. First line treatment with cladribine or fludarabine represents a 3 level of evidence (Treon 2006). In patients with WM resistant to alkylating agents, 2-chlorodeaoxyadenosine and fludarabine, respectively, produced a 40% and 50% response rate. Also corticosteroids are helpful in these patients (Jane 1988), with a median survival of 5 years (Kyle 1987). The synergism between purine analogues and alkylating agents suggests the use of fludarabine and cyclophosphamide in combination: response rate in untreated patients is 85% and in relapsed/refractory patients is 55-89%. ORR of 93% has reported with the combination of cladribrine and cyclophosphamide. Also the use of nucleoside analogs plus alkylators in frontline therapy of WM represents a 3 level of evidence ( Treon 2006). The use of anti-CD20 antibody rituximab as single agents first-line therapy represents type 2 level of evidence in frontline therapy of patients with WM. In at least 6 studies, including 7-35 previously treated WM patients, rituximab has been associated with variable response rates, ranging from 29% to 65% (Dimopoulos 2005; Weber 1999; Foran 2000; Treon 2001; Dimopoulos 2002; Treon 2005; Gertz 2004). Time to response after rituximab is slow; in many patients, a transient increase of serum IgM may occur immediately following initiation of Rituximab. Patients with baseline serum IgM levels of greater than 50 g/L or serum viscosity of greater than 3.5 centipoise (cp), may be particularly at risk for a hyperviscosity-related event. So, rituximab as single agent therapy is not recommended in patients with hyperviscosity symptoms. Plasmapheresis should be considered in advance of rituximab therapy, in these patients. rituximab in combination therapy with chemotherapy is effective and several studies are closed or ongoing. Rituximab in association with cladribine and cyclophosphamide obtained in 17 untreated patients 94% of PR and CR, and with a median follow-up of 21 months, no patients relapsed ( Weber 2003). Complete Response was 7% and Partial Response 74% in a study by the WMCTG in which rituximab was administered in combination with fludarabine in 43 WM patients in frontline or relapsed (Treon 2004). That association between rituximab and cladribine and cyclophosphamide or rituximab and fludarabine represent a type 2 level of evidence. Studies with fludarabine in combination with cyclophosphamide and antiCD20 rituximab or with pentostatin in combination with cyclophosphamide and rituximab are ongoing; preliminary results show encouraging data. Those associations represent a type 3 level of evidence. The combination therapy R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) represent a type 2 level of evidence. In a randomized frontline study conducted by GLSG involving 72 patients, a significantly higher response rate (94% vs. 69%) was observed among patients receiving CHOP-R vs CHOP respectively (Buske 2004). Since the risk of leukemia related to alkylating agents, chemotherapy should be discontinued in patients who have been treated for 2 years in whom the disease has reached a plateau state. Patients should be followed closely, and chemotherapy reinstituted when the disease progresses. Symptomatic hyperviscosity should be treated with plasmapheresis, until the patient is symptomatic. The plasma should be replaced with albumin rather than with plasma.

6.4 Treatment of relapsed or refractory Waldenstrom’s macroglobulinemia

Standard treatment in relapsed or refractory WM is controversial. In the majority of prospective trials the treatment depends on prior treatment, duration of the time-to-relapse, patient’s age, and histologic findings at relapse. To use again the same strategy used as first-line treatment is suitable for individual clinical use on a type R basis in aged patients with a long time-to-relapse and without high-grade transformation. In patients with a shorter time-to-relapse, anthracycline-containing chemotherapy, that is CHOP or CHOP-like regimens, or purine analogue alone or in combination should be used. No definitive conclusion on the use of high-dose chemotherapy supported by autologous bone marrow transplantation could be done; it may be considered as an investigational option in young patients who achieve a further remission after second-line treatment. Only a very small number of patients with relapsed immunocytoma can be treated with this strategy considering the median age of 65 years for these patients at the time of diagnosis, and the median relapse-free survival of more than 5 years after first-line treatment. Purine analogs, alone or in association, are suitable for individual clinical use on a type 3 level of evidence in patients relapsed after anthracycline-containing primary chemotherapy ( Hochster 1992; Whelan 1991; Zinzani 1993). During the Third International Workshop on WM, the consensus panel also considered options for the treatment of patients with relapsed WM. The panel analyzed the use of alternate first-line agents, the reuse of a first-line agent, the use of combination myelotoxic chemotherapy and the use of Thalidomide as a single agent or in combination therapy. The novelty of these recommendations was represented by the role of stem cell transplantation in patients with relapsed or refractory WM. The consensus panel affirmed a type 2 level of evidence for high-dose chemotherapy and autologous stem cell transplantation (Table 2) (Dimopoulos 2005). The experience with ASCT in WM is limited and it is based on retrospective studies; the conditioning regimens were variable, such as melphalan alone or in combination with carmustine, etoposide, cytarabine (BEAM), or in combination with cyclophosphamide, or etoposide; TBI was also utilized in various studies. Data indicate that ASCT in WM is feasible, safe and associated with significant cytoreduction. Patients candidates for high-dose chemotherapy should proceed to stem-cell collection before initiation of treatment with nucleoside analogs, because prior exposure to purine analogs may impair stem-cell collection ( Treon 2006;Johnson 2006; Dimopoulos 2005). Allogeneic stem cell-transplantation is also been experimented in patients with relapsed or refractory WM, but limited results are reported. The largest study involved 10 patients; they received a TBI-containing preparative regimen. The treatment related mortality was 40% and 80% of patients obtained an objective response, including major response in 6 patients (Tournilhac 2003; Anagnostopoulos 2006). A nonmyeloablative conditioning regimen involving low-dose TBI at 2 Gy with fludarabine 90 mg/mq and postgrafting immunosuppression was administered on eight patients who had failed a median of four prior regimen of therapy; there was no transplantation-related mortality and all patients allowed a response. Data suggest that this allogeneic stem cell-transplantation after nonmyeloablative conditioning may provide a new treatment options (Maloney 2003 ).

Table 2 Autologous Stem Cell Transplantation in WM
REFERENCE NO. OF PATIENTS MEDIAN AGE (YEARS) DISEASE STATUS RESPONSE (%) CR (%)
DESIKAN 1999 8 58 Relapse 100 13
ANAGNOSTOPOULOS 2001 4 49 Refractory 75 0
TOURNIHAC 2003 18 55 Chemosensitive, n = 14;
Chemoresistant, n = 4
95 11
DREGER 2004 10 51 First response or primary refractory 100 14
FASSAS 2004 21 NA Various phases 100 62

Abbreviations:
WM: Waldenstrom’s Macroglobulinemia
CR: Complete Response

Reprinted with permission from the American Society of Clinical Oncology” from Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. Diagnosis and Management of Waldenstrom’s Macroglobulinemia. J Clin Oncol 2005; 23(7): 1564-1577.

6.5 New drugs and combinations in Waldenstrom’s macroglobulinemia

Besides rituximab, other monoclonal antibodies are under investigation. Radiolabeled anti-CD20 antibodies are used in patients without extensive bone marrow involvement. Also the anti-CD52 antibody alemtuzumab is active in pretreated patients with WM ( Owen 2005). Studies with anti-CD22 and anti-CD40 are ongoing. New drugs are under investigation in several ongoing studies. Thalidomide is active in multiple myeloma, so it has been administered to patients with WM, because of its action in immunomodulation, antiangiogenesis and altered expression of adhesion molecules. In several phase II studies, the time to response of Thalidomide as single agent was short (0.8 – 2.8 months) and there was a lot of side effects, because of high dose (maximum dose 600 mg). Thalidomide has been administered in combination with clarithromicina and dexamethasone, with evidence of activity in relapsed WM (Coleman 2003). Clinical evaluation of thalidomide derivates, such as CC-5013 (lenalidomide) and CC-4047, are ongoing. Bortezomib (PS-341) at clinically relevant doses induces growth arrest and apoptosis of both the WM-WSU (WM-Waine State University) cell line model and tumour cells freshly isolated from WM patients. Studies of phase II are ongoing and preliminary data suggest the activity of bortezomib in patients with refractory WM ( Dimopoulos 2005). Clinical trials of phase I are ongoing for studying the efficacy and safety of oblimersen sodium (G3139), an antisense phosphorothioate oligonucleotide compound designed specifically to bind the first six codons of the human Bcl-2 mRNA sequence (Gertz 2005). Other agents, like sildenafil that reduces serum monoclonal protein increasing the spontaneous apoptosis rate of lymphoplasmacytic cells and ansamycines, which inhibit hsp-90 molecular chaperone, histone deacetylase inhibitors and thiazolidinediones, are currently under investigation (Treon 2006; Dimopoulos 2005).

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Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
mail: ferreri.andres@hsr.it

Dr. Silvia Montoto (Reviewer)
Institute of Cancer and the CR-UK Clinical Centre Barts and The London Queen Mary’s School of Medicine and Dentistry – London, UK
mail: silvia.montoto@cancer.org.uk

Dr. Umberto Vitolo (Author)
Azienda Ospedaliera S.Giovanni Battista (Molinette)
mail: uvitolo@molinette.piemonte.it