WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA

Steven P. Treon¹, Giampaolo Merlini²

Bing Center for Waldenstrom’s Macroglobulinemia, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA¹; and Department of Biochemistry at the University of Pavia, and Biotechnology Research Laboratories, University Hospital Policlinico San Matteo, Pavia, ITALY ²

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Table of Contents

Epidemiology and Etiology
Cytogenetic findings
Nature of the Clonal Cell
Bone Marrow Microenvironment
Clinical Features
Morbidity Mediated by the Effects of IgM
Hyperviscosity syndrome
Cryoglobulinemia
Auto-Antibody Activity
IgM related neuropathy
Cold agglutinin hemolytic anemia
Tissue deposition
Manifestations related to tissue infiltration by neoplastic cells
Laboratory Investigations and Findings
Hematological abnormalities
Biochemical investigations
Serum viscosity
Bone marrow findings
Other investigations
Prognosis
Treatment of Waldenstrom's Macroglobulinemia
Frontline Therapy
Alkylator-based therapy (chlorambucil)
Nucleoside analogue therapy (fludarabine, cladribine)
CD20-directed antibody therapy - Rituximab (Rituxan®)
Combination Therapies
Salvage Therapy Including Novel Agents
Proteosome inhibitor - Bortezomib (Velcade®)
CD52-directed antibody therapy - Alemtuzumab (Campath-1H®)
Thalidomide and Lenalidomide
High-Dose Therapy and Stem Cell Transplantation
Response Criteria in Waldenstrom's Macroglobulinemia
References
Tables
Figures

Introduction

Waldenström’s macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphocytes, lymphoplasmacytic cells and plasma cells which secrete a monoclonal IgM protein (Figure 1).¹ This condition is considered to correspond to the lymphoplasmacytic lymphoma (LPL) as defined by the Revised European American Lymphoma (REAL) and World Health Organisation classification systems.^2,3 Most cases of LPL are WM, with less than 5% of cases made up of IgA, IgG and non-secreting LPL.

Epidemiology and Etiology

WM is an uncommon disease, with a reported age-adjusted incidence rate of 3.4 per million among males and 1.7 per million among females in the USA, and a geometrical increase with age.^4,5 The incidence rate for WM is higher among Caucasians, with African descendants representing only 5% of all patients. Genetic factors appear to be an important factor to the pathogenesis of WM. Approximately 20% of WM patients have an Ashkenazi (Eastern European) Jewish ethnic background, and there have been numerous reports of familiar disease, including multigenerational clustering of WM and other B-cell lymphoproliferative diseases.^6-10 In a recent study, approximately 20% of 257 serial WM patients presenting to a tertiary referral had a first degree relative with either WM or another B-cell disorder.⁷ Frequent familiar association with other immunological disorders in healthy relatives, including hypogammaglobulinemia and hypergammaglobulinemia (particularly polyclonal IgM), autoantibody (particularly to thyroid) production, and manifestation of hyperactive B cells have also been reported.^9,10  Increased expression of the bcl-2 gene with enhanced B-cell survival may underlie the increased immunoglobulin synthesis in familial WM.⁹ The role of environmental factors in WM remains to be clarified, but chronic antigenic stimulation from infections, certain drug and agent orange exposures remain suspect. An etiological role for hepatitis C virus (HCV) infection has been suggested though in a recent study examining one-hundred consecutive patients with WM, no association could be established using both serological and molecular diagnostic studies for HCV infection ^11-13

Biology

Cytogenetic findings

Several studies, usually performed on limited series of patients, have been published on cytogenetic findings in WM demonstrating a great variety of numerical and structural chromosome abnormalities. Numerical losses involving chromosomes 17, 18, 19, 20, 21, 22, X, and Y have been commonly observed, though gains in chromosomes 3, 4, and 12 have also been reported.^7,14-19 Chromosome 6q deletions encompassing 6q21-22 have been observed in up to half of WM patients, and at a comparable frequency amongst patients with and without a familial history.^7,19 The presence of 6q deletions have been suggested in one study to discern patients with WM from those with IgM monoclonal gammopathy of unknown significance (MGUS), and to have potential prognostic significance though others have reported no prognostic significance to the presence of 6q deletions in WM^20,21. While 6q deletions have been reported in other B-cell malignancies, several candidate tumor suppressor genes in this region are under investigation in WM patients including BLIMP-1²², a master regulatory gene implicated in lymphoplasmacytic differentiation. Notable, however, is the absence of IgH switch region rearrangements in WM, a finding which may be used to discern cases of IgM myeloma where IgH switch region rearrangements are a predominant feature.²³