From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

Review in translational hematology

Waldenström macroglobulinemia
Arun Vijay1 and Morie A. Gertz2
1Austin Medical Center–Mayo Health System, Austin, MN; 2Division of Hematology, Mayo Clinic, Rochester, MN

In the past 36 months, new developments
have occurred both in the understanding
of the biology of Waldenström macro-
globulinemia (WM) and in therapeutic op-
tions for WM. Here, we review the classifi-
cation, clinical features, and diagnostic
criteria of the disease. WM is a B-cell
neoplasm characterized by lymphoplas-
macytic infiltration of the bone marrow
and a monoclonal immunoglobulin M
(IgM) protein. The symptoms of WM are
attributable to the extent of tumor infiltra-
tion and to elevated IgM levels. The most
common symptom is fatigue attributable
to anemia. The prognostic factors predic-
tive of survival include the patient’s age,
␤2-microglobulin level, monoclonal pro-
tein level, hemoglobin concentration, and
platelet count. Therapy is postponed for
asymptomatic patients, and progressive
anemia is the most common indication
for initiation of treatment. The main thera-
peutic options include alkylating agents,
nucleoside analogues, and rituximab.
Studies involving combination chemo-
therapy are ongoing, and preliminary re-
sults are encouraging. No specific agent
or regimen has been shown to be supe-
rior to another for treatment of WM. Novel
agents such as bortezomib, perifosine,
atacicept, oblimersen sodium, and tositu-
momab show promise as rational tar-
geted therapy for WM. (Blood. 2007;109:
5096-5103)
© 2007 by The American Society of Hematology

Introduction
Nearly 63 years have passed since Jan Gosta Waldenström first
described 2 patients with oronasal bleeding, lymphadenopathy, anemia
and thrombocytopenia, elevated erythrocyte sedimentation rate, high
serum viscosity, normal bone radiographs, and bone marrow showing
predominantly lymphoid cells.1 At a time when paper electrophoresis
was unheard of, he attributed hyperviscosity symptoms to an abnormal
high-molecular-weight serum protein. These preliminary observations
proved to be the cornerstones of the widely recognized but relatively
uncommon diagnosis of Waldenström macroglobulinemia (WM).
The abnormal high-molecular-weight serum protein subsequently
was shown to be monoclonal immunoglobulin M (IgM).
Definition and pathology
WM is a malignant lymphoplasmo-proliferative disorder with
monoclonal pentameric IgM production. The most consistent
feature of the bone marrow or lymph nodes of patients with WM is
the presence of pleomorphic B-lineage cells at different stages of
maturation, such as small lymphocytes, lymphoplasmacytoid cells
(abundant basophilic cytoplasm but lymphocyte-like nuclei), and
plasma cells.2 Bone marrow is infiltrated in a predominantly
intertrabecular pattern. A significant increase in the number of mast
cells has been noted in bone marrow biopsies of WM patients.3
Bone marrow mast cells of WM patients overexpress the CD40
ligand (CD154), which is a potent inducer of B-cell expansion.
Classification
WM was initially defined in broad terms with the Kiel classifica-
tion4 as a lymphoma of Ig-secreting cells, often associated with a
paraproteinemia. Subsequently, WM was combined with lympho-
plasmacytic lymphoma (LPL) and designated LPL/WM in the
Revised European-American Lymphoma5 and World Health Orga-
nization (WHO)6 classifications. The consensus group at the
Second International Workshop on WM in 20027 redefined WM as
a distinct clinicopathologic entity characterized by bone marrow
infiltration by LPL and IgM monoclonal gammopathy.
Incidence
WM has an overall incidence of approximately 3 per million
persons per year, accounting for approximately 1% to 2% of
hematologic cancers.8,9 The incidence of WM is higher among
whites, with blacks representing only 5% of all patients.10 In large
series of patients, the median age varies between 63 and 68 years,
with 55% to 70% men.11 WM remains incurable, and most patients
die of disease progression, with a median survival of 5 years.12
Because of the late age of presentation of WM, half of the patients
succumb to causes unrelated to WM.
Etiology and predisposing factors
WM is believed to be predominantly a sporadic disease. Its cause is
unknown, but various reports of multigenerational clustering and
familial patterns indicate the possible role of a single genetic
defect.13 Treon et al14 analyzed 257 consecutive and unrelated
patients with WM: 48 (18.7%) had at least 1 first-degree relative
with either WM or another B-cell disorder. Moreover, patients with
a familial history of WM or a plasma cell disorder received the
diagnosis at a younger age and with greater bone marrow involve-
ment. Deletions in 6q21-22.1 were confirmed in most WM patients
regardless of family history. In short, a high degree of clustering of

Submitted November 1, 2006; accepted February 7, 2007. Prepublished 2006-11-055012.

online as Blood First Edition Paper, February 21, 2007; DOI 10.1182/blood- © 2007 by The American Society of Hematology

5096 BLOOD, 15 JUNE 2007 䡠 VOLUME 109, NUMBER 12

 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
BLOOD, 15 JUNE 2007 䡠 VOLUME 109, NUMBER 12
B-cell disorders was seen among first-degree relatives of patients
with WM.
The main risk factor for the development of WM is pre-existing
IgM–monoclonal gammopathy of undetermined significance
(MGUS) (46 times higher relative risk than for the general
population).15 Morra et al16 showed a progressive increase in the
risk of transformation from asymptomatic IgM-MGUS to symptom-
atic WM, with increasing IgM levels.
A possible association between hepatitis C virus and WM had
been suggested,17 but this has been negated recently by Leleu et
al.18 Reports of links between human herpesvirus-8 and WM are
unconfirmed.
Origin
The origin of the B-cell clone has been long debated. Distinct
B-cell subsets have been demonstrated in the bone marrow,
marginal zone of the spleen and lymph nodes, and circulating in the
peripheral blood.19 Analysis of 14q32 by fluorescence in situ
hybridization (FISH) and Southern blot indicates the absence of Ig
heavy chain (IgH) rearrangements in WM.20 Postswitch clonotypic
Ig (IgG or IgA) is undetectable in WM B cells, confirming the
absence of isotype switch events by deletional recombination.21-23
With the use of variable region (V) gene analysis, evidence shows
that VH genes are somatically mutated in WM. Most WM VDJ
sequences from the VH3/JH4 gene families are hypermutated and
lack intraclonal heterogeneity.21,23 In contrast, one case has been
reported in which WM cells have shown functional class switch
recombination.24 This favors the hypothesis that WM cells have
normal class switch recombination machinery but defective initia-
tion of the switching process.
Cytogenetic abnormalities
The only recurrent abnormality identified by Schop et al20,25 was
deletion of the long arm of chromosome 6 in 55% of cases. In
contrast, FISH analysis by Terre et al26 on 39 WM cases found 6q
deletions in only 21%, and trisomy 4 was the most recurrent
chromosomal abnormality (18%). In a study involving 37 patients
with LPL/WM, Mansoor et al27 reported that the most common
chromosomal numeric abnormalities were trisomy 5 and mono-
somy 8 in 3 cases each; the most common structural abnormality
was deletion of 6q in 6 cases.
Liu et al28 reported a single case of WM with deletion of 20q as
the sole initial cytogenetic abnormality. Ten cases with plasma cell
dyscrasias and del(20q) were reviewed. None of the cases without
genotoxic chemotherapy exposure had development of myelodys-
plastic syndrome/acute myelogenous leukemia during follow-up.
This suggests that the significance of del(20q) differs depending on
whether it appears at diagnosis or after chemotherapy.
Of the various genes that have been localized to 6q21, BLIMP-1
is postulated to be of importance in WM. BLIMP-1, a tumor-
suppressor gene, is the master gene regulator for B-lymphocytic
cell proliferation and differentiation.29-31 It facilitates the transition
from the mature B-cell stage to the plasma cell stage. Partial or
whole losses in this gene could result in the predisposition for
B-cell malignancies such as WM.
Another area of interest in WM is the B-lymphocyte stimulator
(BLyS), also known as B-cell–activating factor of the tumor
necrosis factor family.32 BLyS is expressed on monocytes and is
WALDENSTRÖM MACROGLOBULINEMIA 5097
critical for maintenance of normal B-cell development and ho-
meostasis.33,34 It is overexpressed in various B-cell malignancies
and has been shown to inhibit apoptosis in malignant B cells.
Moreover, in a study by Elsawa et al,35 lymphoplasmacytic cell
infiltrates in the bone marrow of patients with WM stained positive
for BLyS expression, and serum BLyS levels in patients with WM
were significantly higher than in healthy controls. Because of the
role of BLyS in WM, strategies to inhibit BLyS potentially may
have therapeutic efficacy.
TACI (transmembrane activator and calcium-modulator and
cyclophilin ligand interactor), a TNF-receptor family member
expressed on B lymphocytes, has been shown to have a high
affinity for APRIL (a proliferation-inducing ligand) and BLyS.36
Mutations in TACI signaling are commonly seen in common
variable immune deficiency. In WM, IgG and IgA hypogamma-
globulinemia are more prevalent among cases with mutations in the
TACI signaling process.37
Abnormal expression of hyaluronan synthases (HASs) has
been reported as a possible pathogenetic factor in WM.38
Hyaluronan has a role in malignant cell migration and metasta-
sis. Of the 3 HAS isoenzymes detected in humans, Adamia et
al38 postulated that overexpressed HAS1 and HAS3 form a
hyaluronan matrix around WM cells, thereby preventing their
elimination by the immune system and promoting spread of the
disease. A later report stated that a single nucleotide polymor-
phism in the HAS1 gene resulted in an enhanced risk of WM
development.39 These findings are important considering that
serum hyaluronan levels have been shown to have prognostic
value in multiple myeloma.
Serum interleukin-6 (IL-6) levels have been reported to reflect
disease severity and high tumor burden in patients with WM. It has
also been shown that clonal blood B cells from patients with WM
spontaneously differentiate in vitro to plasma cells through an IL-6
pathway. These findings suggest that IL-6 may be a marker
reflecting tumor burden and response to treatment in WM.40
Immunophenotype
The typical immunophenotype of WM consists of expression of
pan–B-cell surface markers (CD19, CD20, CD22), cytoplasmic
Igs, FMC7, BCL2, PAX5, CD38, and CD79a; CD10 and CD23 are
mostly absent, and CD5 is expressed in 5% to 20% of cases.41
Variations in the immunophenotypic profile exist, but most patients
meet the newly proposed criteria: monoclonal surface Ig positive
(5:1 ␬/␭ ratio), CD19⫹, CD20⫹, CD5⫺, CD10⫺, and CD23⫺.7,42
CD5 positivity does not rule out the diagnosis of WM.
According to the WHO classification, WM cells lack CD23,6
and the 2002 WM consensus group stated that CD23 expression is
found in a minority of patients.7 However, in a retrospective study
of the immunophenotypic profile of 75 patients by Konoplev et
al,43 61% of LPL/WM cases were CD23⫹. As part of the 2004
consensus conference on WM, Hunter et al44 reported the detection
of CD23 in 35% of cases.
The immunophenotypic profile in combination with the pres-
ence of somatic mutations of V genes (IgM) without intraclonal
diversity strongly suggests that the malignant cells in WM originate
from cells at a late stage of differentiation.22 The clonal population
in WM appears to be derived from a B cell arrested after somatic
hypermutation in the germinal center and before terminal differen-
tiation to a plasma cell.45
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
5098 VIJAY AND GERTZ
Signs and symptoms
Most patients with the diagnosis of WM have symptoms attribut-
able to tumor infiltration or monoclonal serum protein (or both).
Symptoms attributable to tumor infiltration
Extensive bone marrow infiltration leads to cytopenias, and
progressive anemia is the most common indication for initiation of
treatment. Lytic bone disease is very uncommon in WM. Although
the neoplastic clone predominantly infiltrates the bone marrow, it
can also infiltrate other organs, including lymph nodes, liver, and
spleen, presenting as organomegalies.46 In rare cases, diffuse
lymphoplasmacytic infiltration of the pulmonary parenchyma can
occur, and patients present with diffuse pulmonary infiltrates,
nodules, or pleural effusion.47 Malignant infiltration of the stomach
and bowel as well as the skull base and orbit has also been
reported.48 Bing-Neel syndrome (long-standing hyperviscosity
altering the vascular permeability and leading to perivascular
malignant infiltration) consists of headache, vertigo, impaired
hearing, ataxia, nystagmus, diplopia, and eventually coma.49 Malig-
nant vitreitis and conjunctival infiltration are rare ocular manifesta-
tions of the disease.50
Symptoms attributable to circulating IgM
The larger size and increased concentration of the monoclonal
protein leads to an increase in vascular resistance and viscosity.
Serum hyperviscosity is the most distinguishing feature of WM,
but it is only observed in less than 15% of patients at diagnosis.51
Symptoms of hyperviscosity usually appear when the normal
serum viscosity of 1.4 to 1.8 cP reaches 4 to 5 cP (corresponding to
a serum IgM level of at least 30 g/L [3 g/dL]) and include
constitutional symptoms, bleeding, and ocular, neurologic, and
cardiovascular manifestations.52 High-output cardiac failure may
develop because of the expanded plasma volume arising from
increased osmotic pressure. Abnormalities in bleeding and clotting
times occur from the interaction of IgM with coagulation factors.
IgM may also coat platelets, thereby impairing their function. The
circulating IgM also may undergo precipitation at cooler tempera-
tures and present as type I or type II cryoglobulinemia. Cryoglobu-
lins may be detected in 20% of patients, but fewer than 5% present
with symptoms such as Raynaud syndrome, arthralgia, purpura,
and skin ulcers.53 Priapism has also been described as an unusual
complication.
Symptoms attributable to tissue deposition of IgM
IgM deposition can occur in glomerular loops, intestine, and skin,
presenting as proteinuria, diarrhea, and macroglobulinemia cutis
(papules and nodules), respectively. Primary amyloidosis due to
deposition of monoclonal light chains occurs mainly in the heart,
peripheral nerves, kidneys, soft tissues, liver, and lungs (in
descending order of frequency).54 Secondary amyloidosis is seen
rarely in WM, with nephrotic syndrome and gastrointestinal
symptoms as the initial presentation.55 Acute renal failure is rare in
WM; in most cases, there is slowly progressive loss of function.56
Although most patients have detectable light chains in the urine,
renal insufficiency and cast nephropathy are rare.11
Symptoms attributable to autoantibody activity of IgM
The IgM protein has been proved to induce various autoimmune
symptoms in WM. In fewer than 10% of patients, the IgM ␬ reacts
BLOOD, 15 JUNE 2007 䡠 VOLUME 109, NUMBER 12
with specific red blood cell antigens at temperatures below 37°C to
produce a chronic immune hemolytic anemia, which is associated
with elevated cold agglutinin titers.57 Schnitzler syndrome is the
term for IgM monoclonal gammopathy associated with urticarial
skin lesions, fever, and arthralgia.58,59 Peripheral neuropathies have
been reported in 15% to 30% of patients with IgM-MGUS or
WM.60 The most commonly encountered symptomatic neuropathy
in WM is symmetric polyneuropathy; other forms include cranial
nerve palsies and mononeuropathies or multineuropathies.61 In a
study of 119 WM patients and 58 controls by Levine et al,62
polyneuropathy symptoms were observed more frequently in
patients with WM (47%) than in controls (9%) (P ⬍.001). Other
less common neuropathies associated with WM include those
related to amyloidosis and cryoglobulinemia. Anti–myelin-
associated glycoprotein (MAG) antibody has been implicated in
the demyelinating neuropathy found in WM.63 Analyses of nerve
tissue from patients with anti-MAG antibodies in nerve or skin
biopsy specimens have demonstrated IgM deposits at the site of
MAG localization. The antibody properties of IgM toward
glomerular basement membrane may present as glomerulonephri-
tis. Angioedema and acquired von Willebrand disease have also
been reported.
Differential diagnosis
The presence of clonal B cells with lymphoplasmacytic differentia-
tion in the bone marrow or a serum monoclonal IgM protein are not
pathognomonic for WM and may be seen in other B-cell lympho-
proliferative disorders including splenic marginal zone lymphoma
(SMZL). With increasing frequency, patients who fulfill the
diagnostic criteria of WM are being diagnosed without having any
symptoms or signs and are classified as having asymptomatic or
smoldering WM.64
Asymptomatic patients with monoclonal IgM and without
morphologic evidence of bone marrow infiltration (⬍ 10% clonal
marrow cells) are classified as having IgM-MGUS, which is the
most common differential diagnosis for patients with an IgM
monoclonal protein. Some patients may have detectable bone
marrow clonal B cells by flow cytometry but no morphologic
evidence of bone marrow infiltration at trephine biopsy. These
patients should be classified as having IgM-MGUS and monitored
without therapeutic intervention.65 Results from FISH studies
indicate that deletion of the long arm of chromosome 6 (6q⫺) is not
seen in IgM-MGUS, and 6q⫺ has been suggested as a clinical
marker to distinguish WM from IgM-MGUS.25
SMZL can be distinguished from WM on the basis of immuno-
phenotypic and molecular cytogenetic studies. Ocio et al66 demon-
strated that CD22 and CD11c were overexpressed in patients with
SMZL, whereas CD25 was more common in WM (88% vs 44%).
The CD103 antigen (which was always negative in WM) was
positive in 40% of SMZL cases. The chromosomal abnormality
most commonly seen in WM was 6q deletion, whereas in SMZL, it
was the loss of 7q along with ⫹3q and ⫹5q.
The clinical differentiation of multiple myeloma (MM) from
WM is straightforward. When a patient presents with features
typical of MM and an IgM component, a diagnosis of IgM-MM is
made. The distinction between IgM-MM and WM is based on the
pure plasma cell morphology in myeloma and presence of lytic
bone lesions in myeloma. Renal insufficiency is more common in
IgM-MM than in WM. Typical WM expresses all the B-cell
antigens (CD19, CD20, and CD22), whereas IgM-MM typically
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BLOOD, 15 JUNE 2007 䡠 VOLUME 109, NUMBER 12
expresses plasma cell antigens CD38 and CD138, which are absent
in WM. IgH gene translocations are more common in IgM-MM,67
particularly t(11;14)(q13;q32).
B-cell chronic lymphocytic leukemia (CLL) may mimic WM
clinically. The most common physical finding in CLL is lymphad-
enopathy. Morphology and immunophenotyping are adequate to
diagnose CLL. Lymphocytes are typically small and mature,
without visible nucleoli, and smudge cells are characteristic.68 The
lymphocytes in CLL are positive for CD5 and CD23, whereas both
are usually negative in WM. The presence of strong cytoplasmic Ig
in WM also helps in making the distinction.6 Patients with CLL
frequently have IgM-MGUS.69
The evolution of WM to diffuse large B-cell lymphoma
(DLBCL) as a result of histologic transformation has been de-
scribed.70 Onset of DLBCL is usually characterized by an aggres-
sive clinical course and usually manifests as worsening constitu-
tional symptoms, profound cytopenias, extramedullary disease, and
organomegaly. It is also associated with a poor outcome. The
clinicopathologic features at diagnosis of WM do not predict the
risk of DLBCL.70 Ig light chain expression is usually identical in
WM and DLBCL.
Diagnosis
In practice, a surface IgM-positive CD5⫺CD10⫺CD19⫹CD20⫹
CD23⫺ immunophenotype in association with a nonparatrabecular
pattern of infiltration is diagnostic of WM.41,71 The diagnostic
criteria as stated by Owen71 are summarized in Table 1. The various
diagnostic studies required in daily practice for suspected cases of
WM are summarized in Table 2.
Prognosis
The median survival of patients with WM ranges between 5 and 10
years in different series. Several studies have evaluated the effects
of different clinical and laboratory variables on patient outcome.72
Age, hemoglobin concentration, serum albumin level, and ␤2-
microglobulin level were identified as the predominant outcome
predictors in these studies.73 Most of these studies concluded that
IgM levels had no prognostic value.74
An International Prognostic Scoring System was presented at
the 2006 American Society of Hematology panel as a staging
system for survival for symptomatic patients in need of therapy.75
The parameters used to stratify risk were age older than 65 years,
␤2-microglobulin level higher than 3 mg/L, monoclonal protein
level higher than 70 g/L (7.0 g/dL), hemoglobin concentration less
than 115 g/L (11.5 g/dL), and platelet count less than 100 ⫻ 109/L.
Low risk was defined as the presence of fewer than 1 adverse
Table 1. Diagnostic criteria for Waldenström macroglobulinemia
IgM monoclonal gammopathy of any concentration
Bone marrow infiltration by small lymphocytes showing plasmacytoid or plasma cell
differentiation
Intertrabecular pattern of bone marrow infiltration
Surface IgM⫹ CD5⫾CD10⫺CD19⫹CD20⫹CD22⫹CD23⫺CD25⫹CD27⫹FMC7⫹
CD103⫺CD138⫺ immunophenotype*
From Owen et al.7 Used with permission.
Ig indicates immunoglobulin.
*Variations from this phenotypic profile can occur, and care must be taken to
satisfactorily exclude other lymphoproliferative disorders. This is particularly relevant
in those that express CD5.
WALDENSTRÖM MACROGLOBULINEMIA 5099
Table 2. Diagnostic approach to confirm a suspected case of
Waldenström macroglobulinemia
1. Serum protein electrophoresis.
2. Immunofixation—to characterize the type of light and heavy chains.
3. 24-Hour urine collection for protein electrophoresis—40%-80% have detectable
Bence Jones proteinuria.
4. Serum ␤2-microglobulin—for prognostic evaluation.
5. Bone marrow biopsy—intratrabecular monoclonal lymphoplasmacytic infiltrate,
ranging from predominantly lymphocytic to lymphoplasmacytic to overt plasma
cells.
6. Cytogenetic studies—optional.
7. Computed tomography of the abdomen and pelvis—to detect organomegaly and
lymphadenopathy. (Skeletal surveys and bone scans are not necessary in
absence of symptoms, since lytic bone lesions are unusual.)
8. Blood or serum viscosity—if signs and symptoms of hyperviscosity syndrome are
present or IgM ⬎ 5000.
characteristic except age; high risk, as the presence of more than 2
adverse characteristics; the remaining patients with 2 adverse
characteristics or older than 65 years had intermediate risk.
Treatment
The aim of treatment is to improve the quality and duration of life
with minimal adverse effects in the most cost-effective manner.
Whether achievement of complete remission confers clinical
benefit is still debatable.
Whom to treat
The Third International Workshop on WM76 affirmed the previous
consensus panel’s recommendations77 that treatment must be
reserved for symptomatic patients and should not be initiated on the
basis of serum monoclonal protein levels alone. Some of the
considerations for initiation of treatment include hemoglobin
concentration less than 100 g/L, platelet count less than 100 ⫻ 109/
L, significant adenopathy or organomegaly, symptomatic hypervis-
cosity, severe neuropathy, amyloidosis, cryoglobulinemia, cold-
agglutinin disease, or evidence of disease transformation.
Nevertheless, a serum monoclonal protein level higher than 50 g/L
places patients at considerable risk of hyperviscosity. This finding
requires a thorough history and physical and funduscopic examina-
tions to diagnose early symptoms and signs of hyperviscosity, and
treatment should not be postponed. Therapeutic outcomes should
be evaluated using updated consensus panel criteria.76
Treatment options
The main choices for primary treatment of WM are alkylating
agents (chlorambucil, cyclophosphamide, melphalan), purine ana-
logues (cladribine, fludarabine), and monoclonal antibody (ritux-
imab [anti-CD20]). Plasma exchange (1-1.5 volume) is indicated
for the acute management of patients with symptoms of hypervis-
cosity because 80% of the IgM protein is intravascular. Patients
may be candidates for initial combination therapy with purine
nucleoside analogues or antibody therapy.76 Table 3 summarizes
the largest therapeutic trials, including their overall response rates
and median response duration.
Chlorambucil (0.1 mg/kg) was the first agent used, with
response rates varying between 31% and 92%.78,94 The most
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5100 VIJAY AND GERTZ BLOOD, 15 JUNE 2007 䡠 VOLUME 109, NUMBER 12

Table 3. Therapeutic studies in Waldenström macroglobulinemia

No. of ORR,
Study Regimen patients % MS or MRD, mo

Facon et al78 Chlorambucil 128 31 MS, 60

Dimopoulos et al79 Cladribine 26 85 MRD, 13
Dhodapkar et al80 Fludarabine 118 38 OS 5 y, 62%
Gertz et al81 Rituximab 34 35 MRD, 27
Petrucci et al82 Melphalan, cyclophosphamide, chlorambucil, prednisolone 31 68 EFS, 66
Case et al83 Carmustine, cyclophosphamide, vincristine, melphalan, prednisolone 33 82 MRD, 43 for CR and 39 for PR
Dimopoulos and Alexanian84 Cyclophosphamide, vincristine, prednisolone 16 44 MRD, 36
CHOP 20 65 MRD, 88
Leblond et al85 CAP (pretreated with an alkylating agent) 45 11 MRD, 3 and OS, 45
Hunter et al86 CHOP/rituximab 13 77 90% remain in remission at 9 mo
Dimopoulos et al87 Dexamethasone, cyclophosphamide, rituximab 34 78 90% progression free at 18 mo
Annibali et al88 Melphalan, cyclophosphamide, prednisone 72 87 EFS, 47
Weber et al89 Cladribine, cyclophosphamide, rituximab 27 94 MRD, 60
Cladribine, cyclophosphamide 37 84 MRD, 36
Tam et al90 Fludarabine, cyclophosphamide, rituximab 5 80 MRD, 39
Fludarabine, cyclophosphamide 9 88 MRD, 38
Tamburini et al91 Fludarabine, cyclophosphamide 49 78 MRD, 27
Branagan et al92 Thalidomide, rituximab 23 68 No relapses at 10 mo median
Hensel et al93 Pentostatin, cyclophosphamide, rituximab 17 90 No patient had relapse at publication time

Data from Treon et al.76

ORR indicates overall response rate; MS, median survival; MRD, median response duration; OS, overall survival; EFS, event-free survival; CR, complete response; PR,
partial response; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; and CAP, cyclophosphamide, doxorubicin, prednisone.

common complication of therapy with alkylating agents is develop-
ment of myelodysplasia and acute nonlymphocytic leukemia from
therapy-induced chromosomal breakage.95 Cladribine (0.1 mg/kg)
has shown response rates in the range of 44% to 90%.79,96-98
Response rates to fludarabine (30 mg/m2) as initial therapy range
from 38% to 100%.80,99-102 Fludarabine and cladribine are cross-
resistant.96 The principal dose-limiting toxicity of both these agents
is bone marrow suppression and immunosuppression, predisposing
patients to infections. Response rates to rituximab (375 mg/m2)
vary between 20% and 50%.81,103-107 Rituximab may be regarded as
a reasonable choice for treating patients with IgM autoantibody-
related neuropathies.108 Patients with polyneuropathy associated
with anti-MAG antibodies treated with high-dose rituximab have
shown clinical improvement as well as improvement of nerve
conduction velocities and decreased anti-MAG antibody titers.109
Polymorphisms in the Fc␥RIIIA (CD16) receptor gene may affect
response to rituximab.110 Transient increases in IgM titers have
been reported in 54% of patients after initiation of rituximab
therapy. These levels may persist for up to 4 months and do not
indicate treatment failure, but they may necessitate plasmapheresis
to reduce hyperviscosity, which may result in the loss of the
therapeutic antibody.111,112 Patients who had initial IgM flares had
poorer response rates than those who did not (28% vs 80%).111
Because several cell cycle regulators and modulators of apopto-
sis are degraded through the ubiquitin-proteasome pathway, protea-
some inhibitors such as bortezomib have become the focus of
clinical research in WM. Chen et al113 described 27 patients in
whom bortezomib was found to be active in WM; 21 patients had
syndrome and found to be more potent and also to lack the
neurotoxic and prothrombotic adverse effects of thalidomide.115
High-dose chemoradiotherapy with autologous stem cell transplan-
tation is occasionally used, but the number of patients treated to
date is inadequate to assess its overall role in management.
Pentostatin is useful for patients who may benefit from high-dose
chemotherapy with autologous stem cell transplantation.93,116 Non-
myeloablative allogeneic peripheral blood stem cell transplantation
may be a promising alternative in patients with refractory dis-
ease.117 Splenectomy is rarely indicated, but limited case reports
suggest that it may be helpful for managing symptomatic painful
splenomegaly and hypersplenism.108
The Third International Workshop on WM76 consensus panel
concluded that it was not possible to delineate a particular
first-line therapeutic agent and that the choice must be made
based on individual patient considerations. Alkylating agents
deplete stem cells and hence should not be used among
patients who may be eligible for autologous transplantation. The
results of ongoing studies will help determine the role of
allogeneic or nonmyeloablative allogeneic transplantation in the
treatment of WM.
Novel advances
Other therapeutic options currently being evaluated for WM
include oblimersen sodium (BCL-2 antisense oligonucleotide),118
131I-tositumomab,119 imatinib mesylate (targets signaling through

more than a 25% decrease in IgM.
Experience with the use of thalidomide in WM, as a single agent
or in combination with dexamethasone or clarithromycin, is
limited. Thalidomide is nonmyelosuppressive, immunomodula-
tory, and antiangiogenic and may be a reasonable choice for (1)
patients for whom first-line therapies have failed, (2) those who
have had disease relapse and are not candidates for alkylating or
nucleoside analog therapy, or (3) patients with pancytopenia.114
Lenalidomide has been studied in MM and myelodysplastic
the stem cell factor and platelet-derived growth factor receptors on
WM and mast cells), and dolastatin (microtubule inhibitor).
Dimopoulos et al120 showed that a combination of dexametha-
sone, rituximab, and cyclophosphamide is an active and well-
tolerated treatment for symptomatic patients requiring therapy.
Disease control was achieved in the majority of patients without the
risks of myelosuppression and immunosuppression, which may
occur when nucleoside analogues are used. The interim results of a
study by Treon et al121 suggest that a combination regimen of
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

BLOOD, 15 JUNE 2007 䡠 VOLUME 109, NUMBER 12 WALDENSTRÖM MACROGLOBULINEMIA 5101

bortezomib, dexamethasone, and rituximab is highly active and
well tolerated in the primary treatment of WM.
One pathway that conveys survival signals in mammalian
cells is based on phosphoinositide 3-kinase/Akt. Akt is a
principal signaling protein in the cellular pathways that leads to
muscle hypertrophy and tissue growth. This pathway also has an
important role in the migration, adhesion, and homing of WM in
vitro and in vivo.122 Akt inhibitors such as perifosine lower the
resistance of tumor cells to various therapeutic modalities and
induce apoptosis in WM. Perifosine also activates mitogen-
activated protein kinase pathways and protein kinase C proteins,
thereby promoting cell proliferation. Specific Akt inhibitors
such as triciribine induce cytotoxicity without enhancing MEK/
ERK (mitogen-activated protein kinase kinase/extracellular sig-
nal-regulated kinase) activity. Combining perifosine with MEK
inhibitors or protein kinase C inhibitors such as AZD6244 and
enzastaurin may provide therapeutic advantages in WM. Perifos-
ine in combination with bortezomib, rituximab, and other agents
has been shown to have enhanced cytotoxicity on WM cell
lines.123 Additional clinical trials are required to establish the
efficacy and safety of such combinations.
Rossi et al124 reported a phase 1/2 study of atacicept
(TACI-Ig) in refractory WM. Atacicept acts as a decoy receptor
by binding to and neutralizing soluble BLyS and APRIL, and
preventing these TNF family members from binding to their
cognate receptors (TACI, BCMA, and BAFF-R) on B-cell
tumors, thereby enhancing cytotoxicity. Mast cells may have a
role in tumor cell expansion through constitutive CD154-CD40
signaling; therefore, CD154 blocking agents may prove to be a
therapeutic option in WM.3 Ho et al125 described the role of
sCD27 in the pathogenesis of WM and demonstrated the
feasibility of targeting CD70 and sCD27-CD70 interactions
with the SGN-70 monoclonal antibody.
WM cells in the bone marrow and mast cells express CD52. In a
phase 2 study by Hunter et al,126 alemtuzumab (humanized
monoclonal antibody against CD52) has been reported to be highly
active in WM. Sildenafil citrate has been shown to induce apoptosis
in WM cell lines.127 In a prospective study,128 30 patients with
slowly progressing WM who did not meet consensus eligibility for
active therapy were treated with sildenafil citrate; disease progres-
sion was suppressed in more than half the patients. After 3 months
of therapy, 63% showed a significant decrease in IgM levels and
17% showed a minor response. These results encourage additional
clinical trials.
Conclusion
WM is a B-cell neoplasm characterized by lymphoplasmacytic
infiltration of the bone marrow and elevated serum monoclonal
IgM levels. The symptoms of WM are attributable to the extent
of tumor infiltration and/or elevated IgM levels. The prognostic
factors of significance include the patient’s age, ␤2-microglobu-
lin level, monoclonal protein level, hemoglobin concentration,
and platelet count. Therapy is reserved exclusively for symptom-
atic patients; the main therapeutic options include alkylating
agents, nucleoside analogues, and rituximab. Preliminary results
of ongoing studies involving combination chemotherapy are
encouraging. At present, no specific agent or regimen is superior
to another in the treatment of WM. Other novel agents are being
investigated; their unique mechanisms of action and toxicity
profiles hold promise in the development of rational targeted
therapy in WM.
Acknowledgments
Editing, proofreading, and reference verification were provided by
the Section of Scientific Publications, Mayo Clinic.
Authorship
Contribution: A.V. and M.A.G. contributed to concept and design,
acquisition of data, and analysis and interpretation of data.
Conflict-of-interest disclosure: The authors declare no compet-
ing financial interests.
Correspondence: Morie A. Gertz, Division of Hematology,
Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail:
gertz.morie@mayo.edu.

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 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

2007 109: 5096-5103

doi:10.1182/blood-2006-11-055012 originally published
online February 15, 2007

Waldenström macroglobulinemia
Arun Vijay and Morie A. Gertz

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