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CLINICALREVIEWARTICLE
Waldenstrom’s Macroglobulinemia
By Meletios A. Dimopoulos and Raymond Alexanian
W
ALDENSTROM’S macroglobulinemia (WM) accounts for approximately 2% of hematologic cancers and affects approximately 1,500 Americans each year.
The disease is more frequent among older persons and there
may be a genetic predisposition, as suggested by family clusters.”’ The original description of WM focused on bone
marrow infiltration by plasmacytoid lymphocytes and a
high level of circulating macroglobulin (IgM).3 Many aspects of the biology and clinical features of this disease were
summarized r e ~ e n t l y . This
~ , ~ review focuses on recent advances in the pathogenesis of complications caused by the
elevated IgM and on the treatmentof macroglobulinemic
lymphoma.
cytic leukemia (CLL). Abnormal and complex karyotypes
are common, most frequently consisting of a gain or loss of
chromosomes 10, 12, or 20.’2,13Occasional patients have
been reported with t(8; 14) or t( 14; 18) translocations that
may activate c-myc or bcl-2 oncogene^.^^"^ More studiesof
cytogenetic abnormalities and oncogene expression may
clarify the pathogenesis and implicate featuresof prognostic
significance.
The malignant cells always express monoclonal IgM of
the same light chain type asin the blood. Phenotypic markers reflect a continuum of differentiation, from small lymphocytes bearing large, focal deposits of surface Ig to plasma
cells that contain only intracytoplasmic Ig (Table l). In contrast, thecells ofCLL usually show fainter and more homogeneous expression of both IgM and IgD on the cell memDISEASEFEATURES
brane
without
maturation
of Ig-secretory
In
The most common clinical features of WM are depicted
multiple myeloma, the plasma cells contain intracytoplasin Fig l . Among large series of patients, the median age is63
mic Ig and may express aberrant phenotypes.” In all three
years, 55% are male, and lymphadenopathy or splenomegdiseases,
monoclonal cells are also present in the blood, even
aly occurs in 20% to 40% of patients, especially when comthough
the
absolute lymphocyte count may be normal.
puted tomography or magnetic resonance imaging ofthe abThere is controversy on whether circulating monoclonal
domen has been p e r f ~ r m e d . ~Unusual
-~
sites of tumor
cells represent a spillover of differentiated cells with a liminfiltration include the lungs, the gastrointestinal tract, and
ited
lifespan or include primordial cells capable of sustainthe kin.^.^ Lytic bone lesions were present on standard raing
the
dissemination, asproposed for multiple myeloma.”
diographs in 2%,but bone marrow involvement was shown
Thus, WM and chronic lymphocytic leukemia show differby magnetic resonance imaging in more than 90% of paent forms of a similar lymphoproliferative disorder, with
tienk6 Hypercalcemia occurred in 4% of our patients, with
marked leukemiauncommon in WM and monoclonal IgM
values ranging between 1 1.6 and 12.2 mg/dL, and increased
uncommon
in CLL.
calcitriol levels are the likely cause as in othertypes of lymImmunify.Normal
Igs are less frequently and less
phoma.’ Anemia,
monoclonal
blood lymphocytosis,
markedly depressed than in multiple myeloma; thus, norand Bence Jones proteinuria occur in the majority of pamal IgG exceeded 700 mg/dL in 52% and normal IgA extients.8-1’Bence Jones proteinuria of more than IO mg/d
ceeded
90 mg/dL in 41% of our previously untreated pawas present in 55%, but exceeded 1.0 g/d in only 3% of our
tients.
Cellular
immunity appears to be preserved in most
patients. Serum ,&microglobulin exceeded 4.0 mg/L (norpatients; consistent with a previous report?3 CD4’ lymphomal, <3.0 mg/L) in 17 of 46 patients (37%)and C-reactive
cytes exceeded 0.5 X 109/L in75% of our patients at diagnoprotein was greater than 4.0 mg/L (normal <4.0 mg/L) in 8
sis.
of 12 newly diagnosed patients. The hyperviscosity synMacroglobulinemia without lymphoma. Manypatients
drome is the most common complication of circulating
with monoclonal IgM and without symptomsare diagnosed
IgM, occurring in approximately 15%of patients. Other less
by chance or while being assessed for a complicationcaused
common protein complications include cryoglobulinemia,
by the macroglobulin. Some patientshave monoclonal lymcold agglutinin hemolytic anemia, peripheral neuropathy,
phocytosis of bone marrow and/or blood, and it may be
and amyloidosis (AL), all ofwhich occur morefrequently in
difficult to distinguish between asymptomaticWM and
patients without lymphoma.
monoclonal IgM gammopathy of unknown significance.”
Biology. In most patients, the malignant B cell resemAsymptomatic patients should be monitored without treatbles a plasmacytoid lymphocyte, but many patients have
ment until a complication of circulating IgM or overt lymonly well-differentiated lymphocytes, as in chronic lymphophoproliferative disease becomes evident.
COMPLICATIONS OF CIRCULATING MACROGLOBULIN
From the University of Texas M.D. Anderson Cancer Center.
Houston, TX.
Submitted August 23, 1993;accepted December 3, 1993.
Address reprint requests 10 Raymond Alexanian,MD. University
of Texas M.D. Anderson Cancer Center, Box I , l515 Holcombe
Blvd, Houston, TX 77030.
0 I994 by TheAmerican Society of Hematology.
0006-4971/94/8306-0032$3.00/0
1452
Hyperviscosity syndrome. Hyperviscosity syndrome
caused by IgM virtually always occurs in patientswho have
an underlying lymphoma and is characterized most often
by fatigue, dizziness, blurred vision, and easy bleeding of
mucous membranes. The fundi may have distended, sausage-shaped retinal veins, hemorrhage, and papilledema.’4
The plasma volume is moderately expanded, may reduce
Blood, Vol83, No 6 (March 15). 1994: pp 1452-1459
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1453
WALDENSTROM'S MACROGLOBULINEMIA
Tumor Infiltration
Bone Marrow
Lymph Nodes
Spleen
t
Monoclonal Macroglobulinemia
J
Circulating IgM
Hyperviscosity
Cryoglobulinemia
Cold Agglutinin Anemia
Fig 1. Clinical features of W M .
the hematocrit by as much as 6 vol% less than predicted
from the measured red blood cell (RBC) volume, and may
contribute to high output cardiac failure, especially after
RBC transfusions. Hyperviscosity results from a combination of the increased concentration and more asymmetric
shape of the large, pentameric IgM molecule. Symptoms
usually occur when the measured viscosity is at least four
times that of normal serum when monoclonal IgM concentration usually exceeds 3.0 g/dL; in contrast, symptomatic
hyperviscosity in myeloma usually requires monoclonal
IgA or IgG levels of at least 5.0 g/dL.25326
Measurements of
whole blood viscosity do not provide better insight than
those of serum.27
The easy bleeding ofpatients with WMhas not been well
explained. The cause appears to result from abnormal platelet function induced by the circulating IgM molecule by
mechanisms that remain unclear. Interference with coagu-
Table 1. Phenotvoic Features of Bone
Marrow Malianant Cells
lg
Surface
Cytoplasmic
T-cell-associated antigens
CD5
B-cell-associated antigens
CD10
CD19
CD20
CD2 1
CD22
CD38
PCA 1
CLL
WM
MM
+
0
++
+
++
++
+
0
0
+
++
+
++
+
++
+
0
0
Abbreviation: MM, multiple myeloma.
++
+
++
+
+
0
+
0
0
0
++
+
Tissue IgM
Neuropathy
Glomerular Disease
Amyloidosis
lation proteins have also been described, but this effect appears to be secondary.28
Cryoglobulinemia. Cryoglobulins undergo reversible
precipitation at low temperatures and consist of either
monoclonal IgM (type I) or mixed Ig complexes in which
monoclonal IgM behaves like an antibody against polyclonal IgG (type II).29Type I cryoglobulins are detected in
approximately 15% of patients with overt WM, but less than
5% have symptoms or complications""; type I1 cryoglobulins are usually not associated with any evidence of
lymphoma, but clonal growth may become manifest with
time. For proper diagnosis, blood should be collected,
transported, and separated at 37°C before refrigeration. The
precipitate should be redissolved and electrophoreses conducted to determine the presence of monoclonal and/or
polyclonal Igs and complexes. Cryoglobulinemia may produce Raynaud's syndrome, arthralgia, purpura, peripheral
neuropathy, liver function abnormalities, and renal failure.29,30
The mechanism of cryoprecipitation is not clearly
understood, and theoccurrence of symptoms does not correlate with the temperature at which the cryoprecipitate
forms. The cryoprecipitate may activate complement sequences and thus create an immune complex vasculitis resulting in ischemia of skin, nerve, and renal tissues.
Type I1 cryoglobulinemia is usually idiopathic, but is often associated with hepatitis C virus. These observations
suggest a role for hepatitis C in the pathogenesis of some
cases oftype I1 cryoglobulinemia, and explain the response
of some patients to interferon ( Y . ~ ~ - ~ ~
Cold agglutininhemolytic anemia. In approximately
10%of patients with monoclonal IgM, the abnormalprotein
reacts with specific RBC antigens at temperatures less than
37°C to produce a chronic hemolytic anemia. The hemolysisisusually
mild, extravascular, and associatedwith a
markedly elevated cold agglutinin titer (> 1: 1,OOO), espe-
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1454
DIMOPOULOS ANDALEXANIAN
mine if the neuropathy is demyelinating, as seen in the majority of patients, or axonal.
Approximately one-third of patients with macroglobulinemia, but without neuropathy,demonstrate low titers (< 1 :
400) of anti-MAG and SGPGantibodies by ELISA.4'
Whether prospective screening of such patients for IgM
anti-MAG antibodieswould identify those at risk for future
neurologic complications is unclear.
Renal diseuse. The renal complications of WM are less
common and less severe than those of multiple myeloma
because of the lower frequency and severity of hypercalcemia and Bence Jones proteinuria. A nephrotic syndromeis
the most common renal complication, usually caused by
complicating amyloid~sis.~.~
Nephrosis may also result
from the aggregation and precipitation of IgM molecules on
the endothelial side of the glomerular basement membrane
and their occlusion of the capillary lumen53; the proteinuria
is usually mild and reversible and most patients are asymptomatic. Usually, no antibody activity or glomerular prolifCOMPLICATIONS OF TISSUEDEPOSITION
eration is evident, although rare cases of cryoglobulinemia
Peripheral neuropathy. Approximately 5 % of patients
or an immune-mediated glomerulonephritis have been desCribed.3',54.55
with a sensorimotor peripheral neuropathy have a monoclonal gammopathy, and 5% to 10% of patients with macAmyloidosis (AL). AL has developed in less than 5% of
roglobulinemia develop a chronic, predominantly demypatients with monoclonal IgM.9.56The clinical features are
elinating sensorimotor peripheral n e ~ r o p a t h y . ~Most
~ - ~ ~ similar to those of patients with AL associated with IgG,
patients do not have evidence of lymphoma but clonal
IgA, or light chain production, and thelight chain type has
growth may occur later, indicating the importance of a
been X in 76% of patients. Cardiac, renal, hepatic, and pulscreening electrophoresis in all patients with unexplained
monary complications are common and one or more of
polyneuropathy.Immunocytochemical
studies on sural
these features are usually the cause of death. The incidence
nerve biopsies have shown the monoclonal IgM (usually of
of cardiac and pulmonary involvement was higher in paK type) deposited on the outer layer of the myelin sheath, a
tients with monoclonal IgM than with other Ig types.56AL
sign suggestive of IgM anti-myelin antibody a~tivity.~'
In
should be suspected in all patients with neuropathy, nephroapproximately one-half of the patients with neuropathy, the
sis, cardiomyopathy, or purpura concurrent with any
IgM is an antibody against carbohydrate epitopes of myelinmonoclonal gammopathy.
associated glycoprotein (MAG), as demonstratedby the imTREATMENT
munoblotting t e ~ h n i q u e . ~ ~ .The
~ ' . ~presence
'
of anti-MAG
antibodies canbe detected and quantified by enzyme-linked
IgM-induced complications. When circulating IgM has
immunoabsorbent assay (ELISA), but their specificityis
caused such clinical features as hyperviscosity, cryoglobuconfirmed with imm~noblots.~'
When theIgM monoclonal
linemia, or peripheral neuropathy, plasma exchange
protein immunoreacts with MAG it also reacts with the sultransfusions should be con~idered.~'?~'
Because 80% of IgM
fate-3 glucuronyl paragloboside (SGPG), theprincipal antiis intravascular, plasmaphereses may be conducted expedigenic acidic glycolipid in the ganglioside fraction of periphtiously on an automaticblood cell separator using albumin
eral n e r ~ e ! ~ , ~Because
~
the amount of MAG within
and saline replacement to reduce transfusion-related risks.
peripheral nerves is small, but abundant in the central nerAlthough this procedure rapidly reduces the level of IgM,
vous system, which is not affected, SPGP may be the main
patients with hyperviscosity syndrome also require effective
antigenic
Intraneural
injection
of monoclonal
chemotherapy for the underlying lymphoma to maintain
IgM from patients into feline peripheral nerves induces a
control. In patients who have symptomatic cryoglobulincomplement-dependentdemyelination
with conduction
emia or neuropathy butno evidence of lymphoma, the level
block, implying that theIgM causes human
of the pathogenetic IgM molecule should be reduced for at
A high proportion of IgM monoclonal Igs that donot releast 3 months to assess the effects of the rap^.^',^^ A sequence of plasma exchange followed by chemotherapy (eg,
act with MAG or SPGP immunoreactwith other glycolipid
2 courses of a nucleoside analogue) is the best means of enantigens, such as G M I , C D l basialo
,
GM, or GM2 gangliosuring sustained IgM reduction. Patients with symptomatic
side~.~'.~'
In some patients, the IgM may react with choncryoglobulinemia and withoutlymphomashould
be asdroitin sulfate or sulfa tide^.^'.^'
sessed for the presence of hepatitis C and considered for a
Although the clinical features of neuropathy arevariable,
trial of interferon a.32.33
patients with anti-MAG antibodies usually have a sensory
Lymphoma. Standard criteria for remission after cheor ataxic p ~ l y n e u r o p a t h y . ~In~ ,contrast,
~~
patients with
motherapy have not been defined and controlled therapeunon-MAG-reacting IgM often have a mixed sensorimotor
tic trials have not been conducted for patients with WM:
neuropathy. Electromyographic studies are needed to detercially when tests are conducted at low temperatures. The
protein is usually IgM K and its most common target is the
Ia antigen.34 The best explanation for the pathogenesis is
that conformational changes that occur in the RBC membrane at low temperatures allow epitopes invisible" at 37°C
to become more accessible to IgM antibodie~.~~ degree
The
of cell lysis isin proportion to the amountof complement
activation induced by the low temperature and theIgM concentration. Thus, RBCs may fix complement and agglutinate in colder areas of the circulation, producingRaynaud's
syndrome, acrocyanosis, and livedo reticularis. When the
RBCs return to warmer parts of the body, the cold agglutinin dissociates, but C3d complement remains on theRBCs
and can be shown by the Coombstest. The presence of C3d
complement protects older RBCs from phagocytosis by
macrophages incomparison with younger or transfused
cells.
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1455
WALDENSTROM'SMACROGLOBULINEMIA
thus, treatment has been adapted from establishedprograms
for CLLand low-grade lymphoma. Macroglobulinemiahas
been treated most commonly with a combination of an alkylating agent and a glucocdrticoid, usually chlorambucil
and prednisone. Bothdaily lowdose schedules and intermittent high-dose
schedules
have
been
We
have studied a combination ofchlorambucil(8 mg/m2)and
prednisone (40 mg/m') administered orally dailyfor 10 days
and repeated at 6-week intervals with appropriate dose adjustments. Using criteria of response based on a 75% or
greater reduction of IgM synthesis, lymphadenopathy, and
splenomegaly, 57%of newly diagnosed patients responded
and an additional 15% ofpatients achieved a 50% to 74%
reduction of IgM synthesis (Table 2). Treatment was continued until a maximum reduction of IgM was induced before follow-up without treatment. Relapses were slow, disease recontrol was frequent and prolonged, approximately
20% of patients died from unrelated diseases, and the median survival was 5 years; others have described similar survival times.*"' Approximately 10% of patients achieved a
complete remission as defined by the disappearance of IgM
by immunoelectrophoresis or immunofixation and their
median survival was 1 1 years; complete remission should
also require the elimination of monoclonal lymphocytes
from bone marrow, as for patients with CLL.60The combination ofcyclophosphamide, vincristine, and prednisone or
the same drugs with doxorubicin have given similar results
(Table 2), as in patients withCLL.6' Combinations of
multiple alkylating agents with prednisone, alleged to produce higher responserates and longer s~rviva1,6'~~~
have not
been compared with chlorambucil-prednisonein controlled
studies. Interferons a and y , and glucocorticoids, are each
active in occasional patients with resistant disease but no
trials of these agents have beenconducted in previously untreated
Nucleoside analogues such as fludarabine and 2-chlorodeoxyadenosine(2CdA)have beenstudied in previouslyuntreated patient^.^'.^^ Fludarabine has been administered in a
dose of 25mg/m2intravenously daily for 5 consecutive days
every 4 weeks, and 2CdA in a dose of 0. l mg/kg daily for7
days by continuous infusion through a central venous catheter using a portable pump. For both agents, 79%of patients
responded to as few as 2 courses, 10%of patients achieved a
complete remission, and only 1 of 19 patients has died of
Table 2. Response and Survival of 132 Previously Untreated
Patients with WM
Median
No.
Chlorambucil-prednisone
5.0
57
Cyclophosphamidevincristine-prednisone
Cyclophosphamide-vincristine
prednisone-doxorubicin
Nucleoside analogues
(fludarabine, 2CdA)
Response
Rare(%]
Survival
P
(yr)
P
77
20
65
19
79
NR
Abbreviations: NR, not reached;
NS, differences were not significant.
LPKOP
5
10
15
20
25
Years of Treatment
Fig 2. Cause-specific survival for previously untreated patients
who received chlorambucil-prednisone (LP) or cyclophosphamide,
vincristine, prednisone (COP); or with doxorubicin (CHOP): or nucleoside analogues(2CdA orfludarabine).
WM after a median follow-up of 18 months (Fig 2). Repeated coursesof a nucleoside analogue should be limited to
prevent unpredictable occurrences of severe &-ne marrow
aplasia.
Intracellular phosphorylation by deoxycytidine kinase
converts fludarabine and 2CdA to their active triphosphates. The ratio of deoxycytidine kinase activity to cytoplasmicS'-nucIeotidaseexpression correlates withsubsequent sensitivity to 2CdA in patients withCLL.69 These
parameters may help identify those patients with macroglobulinemia and othersmall celllymphomas who are most
likely to respond to a nucleoside analogue. Whether a program that alternates 2CdA with chlorambucil-prednisone
would be more effective requires further study. Human
macroglobulinemia tumors have been propagated in mice
with severe combined immunodeficiency,providing an important model for the future study of new agents and new
drug combinations.
Prognostic factors. Analyseshave indicated that age
greater than 60 years, male gender, and hemoglobin less
than 10 g/dL were associatedwith a shorter survivalin
WM." Our analysis of 132 previouslyuntreated, symptomatic patients showed age as the only significant prognostic
factor. Patients older than 60 years had a lower response
rate (Fig 3)and a significantlyshorter cause-specific survival
time (Fig 4).In the series of Facon et al," 23%of their patients died of unrelated causes, a figure similar to the 16%
among our patients. Such observations indicate that causespecific survival is the appropriate endpoint inthese studies
becauseit controls for the many deaths dueto unre-
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DIMOPOULOS AND ALEXANIAN
76
L
Primary
Refractory
lated causes among older patients. Consistent standardsfor
cause-specific survival should be applied such as deaths due
to lymphoma, a complication of IgM, or a complication of
therapy. Similar analyses may be useful in the study of CLL
and other diseases that occur among patients of older age
with a long survival time. Patients whose WM was reduced
by at least 75% lived a median of 7.7 years in comparison
with a median of 2.5 years for unresponsive patients ( P <
.Ol), a difference that could be explained by the remission
A
Refractory
Relapse
Fig 3. (A)Response rates of
previously untreated
patients
by age (P < .01). (B) Response
rates to nucleosideanalogues
of patients resistant to alkylating agents (P = ,021.
times of responding patients. A staging system has not been
developed because outcome does not correlate consistently
with the extent of disease as defined by available rneasurements.
illkylaling ugenl-resistanr diseust.. Until recently, few
effective treatments were available for patients whose WM
was resistant to an alkylating agent-glucocorticoid combination. Either fludarabine or 2CdA induced responses in
54% of patients for a median duration of 30
1 00l
80
Fig 4. (A) Cause-specific
survival of previously untreated
patients by age (P < ,011. (B)
Cause-specific survival ofpatients
with
primary
resistant
disease or with disease inresistant relapsewho received a nucleoside analogue (P < .01).
I
l..
1
Relapse
Refractory
c
5
IO
15
20
25
2
Years of Treatment
4
6
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WALDENSTROM‘S MACROGLOBULINEMIA
Patients in resistant relapse despite ongoing therapy were
much less likely to benefit, with only 18%responding to either drug (Fig 4).This accounted for the muchshorter survival of patients in relapse than of those with primary resistant disease. Thus, a nucleoside analogue is the treatmentof
choice for WM that has not responded to an alkylating
agent-steroid combination.With
resistant relapse, new
agents and more intensive chemotherapy shouldbe studied.
Myeloablative therapy with autologous bone marrow or
blood stem cell transplantation has been considered useful
for many patients with multiple myelomaand CLL,70*71
but
no formal studies have been conducted in patients with
WM. As in other lymphoproliferative diseases, the specific
categories of patients (primary resistance, first remission,
etc) that are most likely to benefit substantially should be
identified.
Myelodysplasia and acute myelogeneous leukemia have
appeared after chemotherapy with alkylating agents, but
this complication hasnot yet followed the use of a nucleoside analogue.72Transformation of WM to large-cell lymphoma with less I g M production may also occur, consistent
with clonal evolutionasoccurs
in somepatients with
cLL.73,74
CONCLUSIONS
WM is an uncommon low-grade, small-cell lymphoma
with monoclonal IgM production.Complications result
from tumor infiltration, circulating or tissue-bound monoclonal protein, or a combination of features. Asymptomatic
patients with smoldering IgM can be difficult to distinguish
from those with monoclonal IgM protein of unknown significance. Approximately 10%of patients with monoclonal
IgM have disease features due entirely to the abnormal Ig
but noclear evidence of lymphoma. Plasmaphereses, interferon a,or nucleoside analogue therapy should be considered when complications are caused by circulating IgM.
When overt lymphoma is present, intermittent courses of
chlorambucil and prednisone have induced remissions in
approximately 60% of patients, resulting in a median survival of approximately 5 years. Nucleoside analogues (fludarabine, 2-chlorodeoxyadenosine) are promisingnew agents
that have been effective in 40% of patients with primary resistance to chlorambucil-prednisone and in 80% of newly
diagnosed patients.
ACKNOWLEDGMENT
We are indebtedfor helpful suggestions on malignant cell phenotyping to Dr Linda Pilarski and on peripheral neuropathy to Dr
Marinos Dalakas. We also thank K a y Delasalle for technical assistance and Rose Guevara for preparing the manuscript.
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1994 83: 1452-1459
Waldenstrom's macroglobulinemia
MA Dimopoulos and R Alexanian
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