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CHAPTER 109 in Acta Medica Scandinavica three cases of a disease, he presciently
In 1944, Jan Waldenström, a Swedish physician-scientist, reported
MACROGLOBULINEMIA thought was related to myeloma but for the absence of bone involvement
and the scarcity of plasma cells in the infiltrate of small lymphocytes. He
noted the increase in plasma protein concentration, marked increased
serum viscosity, exaggerated bleeding and retinal hemorrhages, and vir-
Steven P. Treon, Jorge J. Castillo, Zachary R. Hunter, and tually every other feature of the disorder in his case descriptions. In col-
Giampaolo Merlini laboration with a colleague, he showed, using ultracentrifugation and
electrophoresis, that the abundant abnormal protein had a molecular
weight of approximately 1 million and was not an aggregate of smaller
proteins. The disease, which he described with such thoroughness, was
SUMMARY later named in his honor.

Waldenström macroglobulinemia (WM) is an indolent B-cell neoplasm EPIDEMIOLOGY
manifested by the accumulation of clonal immunoglobulin (Ig) M secreting
lymphoplasmacytic cells. MYD88 L265P and CXCR4 WHIM (warts, hypogamma- The age-adjusted incidence rate of WM is 3.4 per 1 million among males
globulinemia, infections, myelokathexis)-like somatic mutations are present and 1.7 per 1 million among females in the United States. It increases in
4,5
in more than 90 percent, and 30 to 35 percent of WM patients, respectively, incidence geometrically with age. The incidence rate is higher among
and impact disease presentation, treatment outcome, and/or overall survival. Americans of European descent. Americans of African descent rep-
Familial predisposition is common in WM. Asymptomatic patients should resent approximately 5 percent of all patients.
Genetic factors play a role in the pathogenesis of WM. Approx-
be observed. Patients with disease-related hemoglobin of less than 10g/dL, imately 20 percent of WM patients are of Ashkenazi-Jewish ethnic
9
platelets less than 100 × 10 /L, bulky adenopathy and/or organomegaly, background. Familial disease has been reported commonly, including
6
symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobu- multigenerational clustering of WM and other B-cell lymphoprolifer-
linemia, cold-agglutinin disease, or transformed disease should be considered ative diseases. 7–10 Approximately 20 percent of 257 sequential patients
for therapy. Plasmapheresis should be used for patients with symptomatic with WM presenting to a tertiary referral center had a first-degree rel-
hyperviscosity, and prerituximab for those with high serum IgM levels to ative with either WM or another B-cell disorder. Familial clustering
9
preempt a symptomatic IgM flare. The treatment choice should take into of WM with other immunologic disorders, including hypogammaglob-
account specific goals of therapy, necessity for rapid disease control, risk of ulinemia and hypergammaglobulinemia (particularly polyclonal IgM),
treatment-related neuropathy, immunosuppression and secondary malignan- autoantibody production (particularly to the thyroid), and manifesta-
cies, and planning for future autologous stem cell transplantation. Frontline tion of hyperactive B cells has also been reported in relatives without
9,10
treatments include rituximab alone or combined with alkylating agents (ben- WM. Increased expression of the BCL-2 gene with enhanced survival
has been observed in B cells from familial patients and their family
damustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfil- members. 10
zomib), or nucleoside analogues (fludarabine, cladribine). In case of relapsed The role of environmental factors is uncertain, but chronic anti-
or treatment-resistant patients, an alternative frontline regimen or autologous genic stimulation from infections and certain drug or chemical expo-
stem cell transplantation can be considered. Novel targeted agents for the sures have been considered but have not reached a level of scientific
treatment of WM include everolimus and ibrutinib. certainty. Hepatitis C virus (HCV) infection was implicated in WM
causality in some series, but in a study of 100 consecutive WM patients
in whom serologic and molecular diagnostic studies for HCV infection
DEFINITION AND HISTORY were performed, no association was found. 11–13

Waldenström macroglobulinemia (WM) is a lymphoid neoplasm result- PATHOGENESIS
ing from the accumulation, predominantly in the marrow, of a clonal
population of lymphocytes, lymphoplasmacytic cells, and plasma cells, NATURE OF THE WALDENSTRÖM
which secrete a monoclonal immunoglobulin (Ig) M. WM corresponds MACROGLOBULINEMIA CLONE
1
to lymphoplasmacytic lymphoma (LPL) as defined in the Revised Euro-
pean-American Lymphoma (REAL) and World Health Organization Examination of the B-cell clone(s) found in the marrow of WM
(WHO) classification systems. Most cases of LPL are WM; less than 5 patients reveals a range of differentiation from small lymphocytes with
2,3
percent of cases are IgA-secreting, IgG-secreting, or nonsecreting LPL. large focal deposits of surface immunoglobulins, to lymphoplasma-
cytic cells, to mature plasma cells that contain intracytoplasmic IgM
(Fig. 109–1). Circulating clonal B cells are often detectable in patients
14
with WM, although lymphocytosis is uncommon. 15,16 WM cells express
Acronyms and Abbreviations: CD16, FcγRIIIa receptor; CD40L, CD40 ligand; CDR, the monoclonal IgM, and some clonal cells also express surface IgD.
17
complement determination region; CHOP, cyclophosphamide, doxorubicin, vincris- The characteristic immunophenotypic profile of WM lymphoplasma-
tine, and prednisone; GM , ganglioside M ; HCV, hepatitis C virus; Ig, immunoglob- cytic cells includes the expression of the pan–B-cell markers CD19,
1
1
ulin; IL, interleukin; κ, kappa light chain; LPL, lymphoplasmacytic lymphoma; MAG, CD20 (including FMC7), CD22, and CD79. 17,18 Expression of CD5,
myelin-associated glycoprotein; R-CHOP, cyclophosphamide, doxorubicin, vincristine, CD10, and CD23 can be present in 10 to 20 percent of cases, and their
prednisone, and rituximab; R-CP, cyclophosphamide, prednisone, and rituximab; presence does not exclude the diagnosis of WM. Multiparameter flow
19
R-CVP, cyclophosphamide, vincristine, prednisone, and rituximab; sCD27, soluble cytometric analysis has also identified CD25 and CD27 as being charac-
CD27; WHO, World Health Organization; WM, Waldenström macroglobulinemia. teristic of the WM clone, and found that a CD22 /CD25 /CD27 /IgM
+
+
dim
+
population may be present among clonal B lymphocytes in patients with

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