Lymphoplasmacytic lymphoma–Waldenstrom's macroglobulinemia

Critical Reviews in Oncology/Hematology 67 (2008) 172–185

Lymphoplasmacytic lymphoma–Waldenstrom’s macroglobulinemia Umberto Vitolo a , Andr´es J.M. Ferreri b,∗ , Silvia Montoto c a

Hematology Unit, Azienda Ospedaliera S. Giovanni Battista “Molinette”, Turin, Italy Unit of Lymphoid Malignancies and Medical Oncology Unit, Department of Oncology, San Raffaele H Scientific Institute, Via Olgettina 60, 20132 Milan, Italy Institute of Cancer and the CR-UK Clinical Centre Barts and The London Queen Mary’s School of Medicine and Dentistry, London, UK b

c

Accepted 27 March 2008

Contents 1. 2. 3.

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Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Immunophenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Genetic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Genomics and proteomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Differential diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Hematological features and complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Hyperviscosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Neurological symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4. Peripheral neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5. Other organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Diagnostic procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Treatment of stages I–II LPL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Treatment of stages III–IV LPL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Frontline treatment of WM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Treatment of relapsed or refractory WM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. New drugs and combinations in WM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract The presence of IgM paraproteinemia in low-grade lymphomas is usually considered a clinical syndrome known as Waldenstrom’s macroglobulinemia (WM). In the WHO classification, WM is associated to lymphoplasmacytic lymphoma (LPL); it is a clinicopathologic ∗

Corresponding author. Tel.: +39 02 26437649; fax: +39 02 26437625. E-mail address: [email protected] (A.J.M. Ferreri).

1040-8428/$ – see front matter © 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.critrevonc.2008.03.008

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entity characterized by a monoclonal expansion of predominantly small B-lymphocytes with variable plasmacytoid differentiation. LPL constitutes less than 5% of all NHL and it is associated with hepatitis C virus infection in 26% of cases. Cells of LPL/WM are B cells positive for monocytic Ig light chains, IgM, pan-B-cell markers, and negative for CD3 and CD103. The t(9;14)(p13;q32) is present in 50% of LPL, and determines PAX-5 over-expression. 6q21 deletion is observed in 42% of cases. LPL occurs in older adults. Clinical presentation usually consists of disseminated disease, but extranodal involvement and leukemic phase are rare. Most WM patients have symptoms attributable to tumour infiltration and/or monoclonal protein. In fact, a monoclonal serum paraprotein of IgM type and hyperviscosity symptoms may occur in more than 20% of cases (WM). Hyperviscosity syndrome is usually manifested by bleeding, blurring or loss of vision, dizziness, headache, and neurologic symptoms. Malignant infiltration of the CNS (Bing–Neel syndrome) is uncommon. LPL/WM is an indolent malignancy that is not usually curable with conventional treatments. The median survival of patients with LPL or WM is 50–60 months, transformation to large cell lymphoma may occur. Stage definition is irrelevant in WM considering that initiation of therapy is decided on the bases of prognostic factors and the development of disease-related symptoms and signs. The main adverse prognostic factors are older age, B symptoms, anemia, low albumin serum levels, raised SGOT, and high beta 2-microglobulin values. Several therapeutic alternatives for newly diagnosed or relapsed LPL/WM are available; however, the best location for every strategy is a matter of investigation. Several new drugs are being assessed in prospective trials. As a significant progress in this field, response criteria and therapeutic recommendations were updated during the Third International Workshop on WM (7–10 October 2004, Paris, France). © 2008 Published by Elsevier Ireland Ltd. Keywords: Indolent lymphomas; Fludarabine; Purine analogs; Hyperviscosity; Paraproteinemia

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 [1,2]. 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 leukemia, mantle-cell, follicular, and marginalzone lymphomas. These cases should be classified according to their major features, and not as lymphoplasmacytoid lymphomas [3]. 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 Waldenstr¨om macroglobulinaemia (WM). WM was originally described in 1944 by Jan G. Waldenstr¨om who reported two patients with oronasal bleeding, anemia, lymphadenopathy, hypergammaglobulinaemia, an elevated sedimentation rate, hyperviscosity, normal bone films, cytopenias, and a bone marrow with a predominantly lymphoid infiltration [4]. 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 lowgrade 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 primarily characterized 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 [3]. LPL/WM is characterized by a monoclonal expansion of predominantly small B-lymphocytes with variable plasmacytoid differentiation; small B-lymphocytes are usually CD5−, CD10− and CD23− and they are associated with serum IgM paraprotein [5].

2. Incidence and risk factors WM constitutes less than 5% of all NHLs and 1–2% of hematological malignancies, with an incidence of ≈3/1,000,000 cases/year [6,7]. Caucasians are predominantly affected, and only 5% of WM are diagnosed in Blacks and other ethnic groups [6–8]. The cause of WM is unknown; no specific occupational or environmental exposures, tobacco or alcohol use have been linked to WM [9]. WM appears to be a sporadic disease, but multiple reports of familial clustering exist [10–19]. A familial history of at least one first-degree relative with either WM or another B-cell disorder has been found in 18.7% of WM patients [19]. Individuals having an IgM monoclonal gammopathy of uncertain significance (MGUS) have 46 times greater risk of developing WM than the general population [20], but factors affecting the progression from IgM MGUS to WM are unknown. Clonal chromosomal abnormalities are frequent in WM [21,22], but their clinical or pathogenic significance is unclear. A recently reported genome wide linkage analysis in

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high-risk families provided strongest evidence of linkage on chromosomes 1q and 4q [23]. There is a single case of secondary WM occurring in a patient treated with radiotherapy for ankylosing spondylitis [24]. The potential link between hepatitis C virus (HCV) and HHV-8 and WM remains controversial. LPL is the non-Hodgkin’s lymphoma subgroup most frequently associated with HCV infection (26% of LPL patients), which does not seem to affect the overall survival, but it affects the clinical expression of the disease, so that the overall quality of life of HCV-positive patients is significantly worse [25]. In an Italian multicenter case–control study using primarily an ELISA-based assay to determine HCV infection, an infection rate of 31% has been observed in 13 cases of LPL [26]. Conversely, Veneri et al. [27] have reported a HCV seroprevalence rate of ≈4% both among 227 patients with IgM monoclonal gammopathy and 60WM patients, which was similar to infection rates in the control population from the same geographical area (northern Italy). Discrepancies in studies analysing the HCV–WM association might be due to differences in the analytical method used considering that WM-related immunodepression may result in humoral immunoparesis and lower sensitivity of ELISA tests detecting anti-HCV antibodies [28]. Recently, Leleu et al. reported the lack of association between HCV and WM in 100 randomly selected WM patients analyzed by both an HCV antibody detection immunoassay and qualitative PCR assay to directly detect HCV presence in serum samples [29].

3. Pathology and biology 3.1. Morphology The tumour consists of a diffuse proliferation of small lymphocytes, plasmacytoid lymphocytes and plasma cells, with or without Dutcher bodies. Plasmacytoid lymphocytes are cells with abundant basophilic cytoplasm, but lymphocytelike nuclei. By definition, this tumour lacks features of B-chronic lymphocytic leukemia, mantle-cell lymphoma, follicular or marginal-zone lymphomas. The growth pattern is often interfollicular with sparing of the sinuses. The bone marrow aspirate in WM is often hypocellular, but biopsy specimens are hypercellular and extensively infiltrated with lymphoid cells. The lymphocytes tend to be small, are often basophilic, and resemble plasma cells. The number of plasma cells is always greater than normal, and normal marrow elements are often decreased. The plasma cells are usually mature (Marchalko type) and may contain cytoplasmic globules (Russell bodies) and intranuclear pseudoinclusions (Dutcher bodies). The number of mast cells is increased, which can be helpful in differentiating macroglobulinemia from lymphoid myeloma or lymphoma. In 39% of patients, the bone marrow aspirate contains a spectrum of small lymphocytes, plasmacytoid lymphocytes and plasma cells; in 39% of patients it contains a predominance of small lymphocytes with fewer plasmacytoid lymphocytes or plasma

cells and in 22% it presents a mixture of small lymphocytes and plasma cells with rare plasmacytoid cells. Mast cells are increased in 26% of patients [30]. The pattern of infiltration is usually nodular (interstitial or paratrabecular), interstitial, mixed or diffuse [5]. 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 [5]. 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 was observed [31]. Additionally, at immunophenotypic study, WM cells are CD25+, CD27+, CD75−, CD79+, CD138−, FMC7+, Bcl2+, Bcl6−, PAX5+, [32–34]. 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 [32,33]. 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 [35]. 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 over-expression 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 [35]. These results are not universally recognized; 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 [5,36] and it is not known to have clinical associations, but a recent study [37] suggested that patients tend to have more aggressive disease and shorter survival. 3.4. Genomics and proteomics The use of gene expression arrays as markers for genomic abnormalities and as tools for disease profiling is useful to

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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 [38]. 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 [38]. 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 [39]. 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 [39]. 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 [40]. 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.

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eral 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 [41]. 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 [42], with a reduced mortality ratio [43]. 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 [43]. 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 [44]. 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 [45]. Importantly, patients with an IgM MGUS with clinical manifestations related to circulating or tissue deposition of IgM, not meeting the criteria for WM (IgMrelated 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 anemia, 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.

3.5. Differential diagnoses 4. Clinical features Differential diagnosis between WM and other B-cell lymphoproliferative (mantle cell lymphoma, B-cell chronic lymphocytic leukemia/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 lymphomas exhibit a more common involvement of gastrointestinal tract in the extranodal form (MALT-type lymphoma), with periph-

4.1. Presentation LPL occurs in older adults, 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) [46,47]. 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 (range 27–82), only 1% of patients are younger than 40

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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 [30]. Monoclonal IgM could result in several complications either when it circulates, accumulates in different tissues or is associated with autoantibody activity. Circulating IgM can be associated with type I cryoglobulinemia or coagulation abnormalities: due to coating of coagulation factors by IgM. Tissue deposition of monoclonal IgM is associated with systemic amyloidosis, macroglobulinemia cutis, gastrointestinal symptoms, like malabsorption, diarrhoea or bleeding, and non-specific proteinuria and glomerular injury. Targets of autoantibody activity of monoclonal IgM can be red blood cell antigens (haemolytic anemia due to primary cold agglutinin disorder), polyclonal IgG (small vessel vasculitis of the skin, nerves, liver, or kidney due to type II cryoglobulinemia), glycoproteins of nerve sheath (peripheral neuropathy), and antibasement membrane (pemphigus, glomerulonephritis, retinitis). 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. 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 anemia [48,49]. The anemia 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 elevated levels of IL-6 [50]. Anemia 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 [48,49], ITP, treatment-related toxicity, splenomegaly, or anti-platelet activity of monoclonal IgM [51]. 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 k-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 [52]. 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 ≤1.8), unexpectedly one third of these patients had not symptoms, but nearly all patients with a viscosity >8 are symptomatic [53]. Risk for hyperviscosity symptoms is high in patients with a serum monoclonal IgM of >50 g/l [30]. 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 [54]. This syndrome (Bing–Neel syndrome) can be divided into a tumoural (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 [55]. 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 [56,57]. 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 [58,59]. Neuropathy in WM seems to be related to the monoclonal IgM, which can acts as an anti-myelin autoantibody, mostly against myelinassociated glycoproteins [60,61], but neuropathy due to amyloidosis, vitamin B12 deficiency and cryoglobulinemia has been also reported.

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4.1.5. Other organs Tumour cells can infiltrate other organs and result in hepatomegaly (20% of cases), splenomegaly (15%) and lymphadenopathy (15–20%) [48,49,62–65]. 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 3–5% of patients with WM have lung involvement, such as diffuse pulmonary infiltrates, nodules, masses 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 [66–68], with associated cardiomyopathy in 44% of cases, and higher incidences of pleural and pulmonary involvement [66,67]. In the subgroup of patients with WMassociated amyloidosis, cardiac amyloidosis represents the most common cause of death [69]. 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 ␤2-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 differen-

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tial 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-myelinassociated glycoprotein (MAG) serology [70]. 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 [30,71]. 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 [46]. Response criteria and therapeutic outcomes were updated during the Third International Workshop on WM (Table 1) [72]. Patients with WM have an overall response rate of 75%. Response rates at

Table 1 Summary of updated response criteria from the 3rd International Workshop on WM Response

Criteria

Complete response

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 complete remission status is required at least 6 weeks part with a second immunofixation At least 50% reduction of serum monoclonal IgM concentration on protein electrophoresis and at least 50% decrease in adenopathy/organomegaly on physical examination or on CT scan. No new symptoms or signs of active disease At least 25% but less than 50% reduction of serum monoclonal IgM by protein electrophoresis. No new symptoms or signs of active disease 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 At least 25% increase in serum monoclonal IgM by protein 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

Partial response Minor response Stable disease Progressive disease

This research was originally published in Kimby et al. [72].

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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 [46]. 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. 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 (<35 g/l), raised SGOT (>41 u/l) and high beta 2-microglobulin values [30,46,70]. 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 [49,73–75]. 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 [76].

6. Treatment 6.1. Treatment of stages I–II LPL Standard therapeutic option for patients with stages 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 involvedfield irradiation is suitable for individual clinical use on a type 3 level of evidence [77,78]. This strategy is associated with a very high response rate and a 12-year 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-year relapse-free survival of 55% and 63%, respectively [79]. In spite of this improvement in relapse-free

survival, a significant difference in overall survival has not been observed. 6.2. Treatment of stages III–IV LPL 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 [80]. 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, median overall survival is longer than 5 years, with a 10-year survival of 70–75%, with spontaneous remissions in up to 23% of cases [81]. Treatment for patients with stages 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 [82]. This strategy is particularly useful in aged patients with small tumour 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% [82–84]. The addition of corticosteroids makes no apparent difference. In spite of a higher response rate [84,85], CVP combination regimen (cyclophosphamide, vincristine and prednisone) shows equivalent efficacy to monochemotherapy. 6.3. Frontline treatment of WM 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

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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 [86]. “Watch and wait” policy is the standard approach to WM in patients without anemia, systemic symptoms, significant hepatosplenomegaly, bulky lesions, or hyperviscosity. 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 [49]. The use of combination chemotherapy including alkylating agents and vinca alkaloids is associated with an 80% response rate [87]. Several additional drugs, like interferon [88], 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% [89] and with cladribine 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 [86]. 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 [90], with a median survival of 5 years [68]. 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 cladribine and cyclophosphamide. Also the use of nucleoside analogs plus alkylators in frontline therapy of WM represents a type 3 level of evidence [86]. The use of anti-CD20 antibody rituximab as single agent first-line therapy represents a 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% [30,91–96]. Response after rituximab is slow, with a median time to best response of 17 months [95]. This may result in underestimated activity of rituximab considering that most clinical trials have been performed with response rates estimated at an earlier time point. In many patients, a transient increase of serum IgM may occur immediately following initiation of rituximab, the so-called “rituximab flare”. 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

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effective and several studies are closed or ongoing. Rituximab in association with cladribine and cyclophosphamide obtained 94% of PR and CR in 17 untreated patients, and with a median follow-up of 21 months, no patients relapsed [97]. 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 patients with newly diagnosed or relapsed WM [98]. 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 use of 2-CDA (cladribine), intravenous cyclophosphamide and oral prednisone has been associated with an ORR of 88% and grade 4 neutropenia in 11% of patients [99]. Dose-escalation of this combination resulted in an ORR of 58% and severe infections in 4% of courses [100]. A combination of fludarabine and cyclophosphamide has been associated with an ORR of 78% and a median time to treatment failure of 27 months [89]; age >65 years and a serum monoclonal protein concentration of <40 g/l were negative predictors of outcome. The combination of pentostatin, cyclophosphamide and rituximab has been associated with an ORR of 65% (pentostatin and cyclophosphamide) and 77% (three drugs) and a complete remission rate of 12% [101]. In a small and heterogeneously treated series, different combinations of fludarabine, cyclophosphamide, mitoxantrone, and/or rituximab have been associated with an ORR of 76%, with a median response duration of 38 months [102]. 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 [103]. 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 WM 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

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Table 2 Autologous stem cell transplantation in WM Reference

No.

Median age (years)

Disease status

ORR (%)

CRR (%)

Desikan et al. [117] Anagnostopoulos et al. [118] Tournilhac et al. [107] Dreger et al. [119] Fassas et al. [120]

8 4 18 10 21

58 49 55 51 NA

Relapse Refractory Chemosensitive (14), chemoresistant (4) First response or primary refractory Various phases

100 75 95 100 100

13 0 11 14 62

ORR: overall response rate; CRR: complete remission rate. Reprinted with permission from the “American Society of Clinical Oncology” from Ref. [30].

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 WM can be treated with this strategy considering the median age of 65 years for these patients at the time of diagnosis, and the median relapsefree 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 [104–106]. 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) [30]. 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 [30,70,86]. 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 [107,108]. 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 achieved a response. Data suggest that this allogeneic stem cell-transplantation after nonmyeloablative conditioning may provide a new treatment option [109]. 6.5. New drugs and combinations in WM 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 [110]. Studies with anti-CD22 and antiCD40 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, high doses of thalidomide (maximum dose 600 mg) as single agent was associated with a short time to response (0.8–2.8 months) and several side effects. Thalidomide has been administered in combination with clarithromicina and dexamethasone, with evidence of activity in relapsed WM [111]. 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 This drug is thought to exert its antitumour effects by deregulating the NF-kB pathway. Studies of phase II are ongoing and preliminary data suggest the activity of bortezomib in patients with refractory WM [30]. When used as single drug or in combination with rituximab and corticosteroids, bortezomib is active against WM, with an ORR of up to 84% [112,113]. The combination of bortezomib, rituximab and dexamethasone, has been associated with a reduction in IgM levels in 100% of cases, equally combined with both minor and major responses [113]. Recently reported in vitro studies suggest a synergistic cytotoxicity on WM cells of bortezomib and the Akt inhibitor, perifosine, both targeting NF-kB through its recruitment to the promoter of its target gene IkB [114]. The combination of these drugs with rituximab further increases their cytotoxic activity [114]. Clinical trials of phase I are ongoing for studying the efficacy and safety of oblimersen sodium (G3139), an antisense phosphorothioate oligonucleotide compound

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designed specifically to bind the first six codons of the human Bcl-2 mRNA sequence [115]. The protein kinase CB inhibitor enzastaurin demonstrated additive cytotoxicity in combination with bortezomib, and synergistic cytotoxicity in combination with fludarabine both in in vitro and in vivo models [116]. Other agents, like sildenafil, which reduces serum monoclonal protein increasing the spontaneous apoptosis rate of lymphoplasmacytic cells and ansamycines, which inhibit hsp-90 molecular chaperone, other than histone deacetylase inhibitors, imatinib mesylate, the anti-CD70 antibody SGN70, and thiazolidinediones, are currently under investigation [30,86] and combinations of these drugs could represent new strategies to be addressed in future WM clinical trials.

Conflict of interest statement Authors have no conflict of interest to be disclosed.

Reviewers Professor Meletios A. Dimopoulos, University of Athens School of Medicine, Department of Clinical Therapeutics, 227 Kifissias Avenue, GR-14561 Athens, Greece. Dr. Eva Kimby, Associate Professor, Karolinska University Hospital Huddinge, Center of Hematology, SE-141 86 Stockholm, Sweden.

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Biographies Umberto Vitolo is the Director of Chemoimmunotherapy Lymphoma Section, Department of Oncology, San Giovanni Battista Hospital, Turin and Italy and member of the scientific commitee of Intergruppo Italiano Linfomi. Andr´es J.M. Ferreri is Coordinator of the Unit of Lymphoid Malignancies and Vice Director of the Medical Oncology Unit, San Raffaele H Scientific Institute, Milan, Italy. Silvia Montoto trained as a Haematologist at the Haematology Department of Hospital Clinic in Barcelona, Spain, and is currently a Senior Lecturer in Medical Oncology at the Medical Oncology Department, St Bartholomew’s Hospital, London.

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