Waldenstrm Macroglobulinemia

Pashtoon Murtaza Kasi, MD, Stephen M. Ansell, MD, PhD, and Morie A. Gertz, MD, MACP

The authors are affiliated with the Mayo Abstract: Waldenstrm macroglobulinemia (WM) is an indolent
Clinic in Rochester, Minnesota. Dr Kasi is low-grade lymphoma characterized by bone marrow infiltration
a fellow in the Division of Hematology/ with lymphoplasmacytic cells associated with a monoclonal immu-
Oncology in the Department of Medicine,
noglobulin M protein. It is considered incurable. The 5-year survival
Dr Ansell is a professor of medicine in the
College of Medicine, and Dr Gertz is a rate for patients with symptomatic WM is 87% for those with low-risk
professor in the College of Medicine and disease, 68% for those with intermediate-risk disease, and 36% for
chair of the Department of Medicine. those with high-risk disease. Owing to recent advances in therapy
with new targeted treatment options, relative survival has improved.
Corresponding author: Insights into mutations in MYD88 L265P and the WHIM-like CXCR4
Morie A. Gertz, MD
have been shown to be significant not just in terms of their diagnos-
Mayo Clinic
200 First St SW tic and prognostic value, but also as potential targets for therapy. For
Rochester, MN 55905 patients with symptomatic WM, the different classes of agents used
E-mail: [email protected] to treat WM include alkylating agents (eg, cyclophosphamide and
Tel: 507-284-2511 chlorambucil), nucleoside analogues (eg, cladribine and fludarabine)
Fax: 507-266-4972 and monoclonal antibodies (eg, rituximab and alemtuzumab). With
an increasing number of novel treatment options available includ-
ing everolimus, bendamustine, bortezomib, ibrutinib, carfilzomib,
lenalidomide, and panobinostat, the optimal timing and introduction
of these options in the absence of phase 3 trials remains controversial.
A treatment algorithm based on Mayo Stratification for Macroglobu-
linemia and Risk-Adapted Therapy (mSMART) and a comparison of
important clinical trials in WM is provided.

Background and Definitions

Described first by the Swedish physician Jan G. Waldenstrm in

1944, Waldenstrm macroglobulinemia (WM) is an indolent
lymphoma characterized by bone marrow infiltration with lympho-
plasmacytic cells associated with a monoclonal immunoglobulin M
(IgM) protein (Figure 1).1-3 It is considered incurable.4,5 The 5-year
survival rates for patients with symptomatic WM based on tools
used for risk stratification are 87%, 68%, and 36%, respectively,
for patients with low-, intermediate-, and high-risk WM.6 With the
Keywords
increasing number of treatment options available for patients with
Bortezomib, everolimus, International Prognostic Scor-
ing System for WM, MYD88, rituximab, Waldenstrm WM, key considerations for practicing oncologists are which agents
macroglobulinemia, WHIM-like CXCR4 to choose and the sequencing of regimens.

56Clinical Advances in Hematology & Oncology Volume 13, Issue 1 January 2015
 WALDENSTRM MACROGLOBULINEMIA

A B

C D
Figure 1. A, Bone marrow biopsy showing infiltration by plasma cells (arrow). B, WM patient retinopathy showing retinal
hemorrhages (arrow) alongside dilated tortuous veins. C, Serum protein electrophoresis M-spike (monoclonal gammopathy,
arrow). D, Immunofixation confirming the monoclonal gammopathy as IgM kappa.

International Prognostic Scoring System Table 1. International Prognostic Scoring System for
Waldenstrm Macroglobulinemia6
Developed by Morel and colleagues, the International
Prognostic Scoring System for Waldenstrm Macro- Adverse Characteristics
globulinemia (ISSWM) helps classify patients with WM Age >65 y
into low-risk, intermediate-risk, and high-risk categories.6
Categorization as noted in Table 1 is based on the presence Hemoglobin 11.5g/dL
of 5 covariates identified from a cohort of 587 patients Platelet count 100 109/L
with symptomatic WM.6 This takes into account the 2-microglobulin >3mg/L
patients age, as well as 4 laboratory parameters identified Monoclonal IgM concentration >7.0g/dL
as adverse variables. This is the accepted scoring system,
Low risk: Age <65 y and 0 or 1 adverse characteristics
which has been validated by other studies.7
Intermediate risk: Age >65 y or 2 adverse characteristics
Serum lactate dehydrogenase, which is an important High risk: More than 2 adverse characteristics
prognostic marker for follicular and large-cell lympho-
IgM, immunoglobulin M; y, years.
mas, is not part of the prognostic scoring system for WM.
Serum lactate dehydrogenase may add to prognostication
among those patients with high-risk WM, according to being older than 65 years automatically places the patient
the ISSWM. Age is a powerful predictor of outcomes; into an intermediate- or high-risk category.

Clinical Advances in Hematology & Oncology Volume 13, Issue 1 January 201557
 KASI ET AL

TLR

CXCR4

MYD88

NFB P13K
pathway pathway

WM

Figure 2. Schematic diagram outlining the important common somatic mutations in WM (MYD88 and CXCR4). In simplistic
terms, MYD88 works through Toll-like receptors to activate the NFB pathway, whereas CXCR4 is a chemokine receptor functioning
through the PI3K pathway.
NFB, nuclear factor B; PI3K, phosphatidylinositol 3-kinase; TLR, Toll-like receptor; WM, Waldenstrm macroglobulinemia.

Response Criteria of 63 years. Older age, black race, and male sex were asso-
For the purpose of this review, we have used the definition ciated with poorer prognosis.9 Similar findings have been
of overall response as a partial response or better (decline reported across other population-based studies and data-
in IgM 50%) for consistency and comparison across bases.10-12 The relative survival has improved in the decade
studies. Response is a predictor of both relapse-free and from 2000 to 2010.8,9,11
overall survival.
Clinical Presentation
Prevalence and Risk Factors
The spectrum of clinical presentation of patients in
WM is a rare disease. According to the Surveillance, Epi- WM can be divided into 2 groups. The first is related
demiology, and End Results database, there were a total to the cytopenias from infiltration of the bone marrow,
of 1835 new cases reported over 2 decades.8 This is an and the second is related to hyperviscosity from the IgM
incidence of 0.38 per 100,000 persons per year. Overall, gammopathy.2 Hyperviscosity (measured in centipoise;
there has been a rising age-adjusted incidence over time.9 normal is 1.8) can present subtly as mild headaches and
WM is twice as common in men as in women.8 The visual disturbances, or severely as seizures and coma.4
incidence also is higher in older age groups (median age of Other signs and symptoms include fatigue, sensory
73 years in whites).8 The incidence in black Americans is neuropathy, and epistaxis.8 Splenomegaly and lymph-
half that of white Americans, with a median age in blacks adenopathy are relatively uncommon.13 Autoimmune

58Clinical Advances in Hematology & Oncology Volume 13, Issue 1 January 2015
 WALDENSTRM MACROGLOBULINEMIA

Table 2. Cytogenetic Abnormalities and Somatic Mutations Table 3. Tests to Be Considered as Part of Workup and
Reported in Patients With Waldenstrm Macroglobulinemia19,24,26 Staging of Waldenstrm Macroglobulinemia

Cytogenetics Mutations Complete blood count

Deletion of long arm (q) of chromosome 6 MYD88 (90%) Serum creatinine
Deletion 13q14 CXCR4 (30%) Serum calcium level
Deletion 17p13 Serum albumin level
Trisomy 4 Serum protein electrophoresis
Gain in the short arm (p) of chromosome 6 Serum IgM monoclonal protein level
M-spike
hemolytic anemia (cold agglutinin disease) also can be 2-microglobulin
seen. Other clinical associations include those related Serum-free light chainsa
to associated c ryoglobulinemias and/or a myloidosis.14-16
CT scan of chest/abdomen/pelvis for evaluation of adenopathy
Schnitzler syndrome (a rare disease characterized by
chronic urticarial rash) has been reported.17 PET/CTa
IgM, immunoglobulin M; CT, computed tomography; PET, positron emission
Biological Insights tomography.
a
Role in evaluation of WM is questionable at this time.
MYD88 L265P and WHIM-Like CXCR4 Mutations
Somatic mutations in MYD88 L265P and the WHIM- General Approach to Patient Evaluation
like CXCR4 are common findings in patients with WM
and have implications for the pathogenesis and outcome Table 3 outlines the tests to be considered as part of evalu-
of patients with WM (Figure 2).18,19,20 MYD88 mutations ating a new patient with WM. Serum monoclonal protein
are seen in more than 90% of patients with WM, and level and bone marrow involvement are key.32 Computed
CXCR4 mutations are seen in up to 30% of patients.21 tomography (CT) scans are used for the assessment of
The particular type (frameshift, nonsense) and combina- adenopathy if clinically indicated. Positron emission
tion of the mutations seen in patients with WM impacts tomography (PET)/CT scans have the potential to offer
the clinical presentation and offers insights into progno- further information about patients with WM, based on
sis and potential drug resistance.22,23 limited case series.32 At present, however, routine use of
18
F-fluorodeoxyglucose-PET/CT imaging is not recom-
Other Cytogenetic Abnormalities and Findings mended and warrants further evaluation.32,33
The cytogenetic abnormalities and somatic mutations
reported in patients with WM24 are outlined in Table Key Considerations Regarding Natural
2. Other gene polymorphisms of predictive potential History and Clinical Management
include the expression of the hCNT1 gene.4,25 In a phase
2 study, human concentrative nucleoside transporter 1 When WM Should Go Untreated
(hCNT1) was predictive of response to cladribine. Dele- Observation is an appropriate option for patients diag-
tion of the long arm of chromosome 6 can be seen in nosed in the absence of symptoms. If the patient is
more than one-third of the patients, but does not appear asymptomatic, an arbitrary IgM number should not
to affect prognosis or survival.26 The monoclonal antibod- trigger initiation of chemotherapy. Symptoms created by
ies rituximab (Rituxan, Genentech/Biogen Idec) and progressive cytopenias, constitutional complaints, and
alemtuzumab are active in patients with WM.27 Specific hyperviscosity syndrome require therapy.
polymorphisms in the FcRIIIA (CD16) receptor have
been shown to be predictive of response to rituximab in Factors Influencing Choice and Timing of Treatment
patients with WM.28,29 Genome-wide expression studies A number of factors influence the choice and timing of a
of these tumors demonstrate an expression pattern closer particular treatment regimen. The overall goal is to allevi-
to that of chronic lymphocytic leukemia than to that of ate symptoms.4 The 4 most common symptoms requiring
multiple myeloma.30 In a large population-based study intervention are hyperviscosity, constitutional/B symp-
from Sweden, patients with IgM monoclonal gammopa- toms, bulky disease, and cytopenias.34 The ISSWM system
thy of unknown significance had a 5-fold increased risk can stratify patients into low-risk, intermediate-risk, and
of developing chronic lymphocytic leukemia, suggesting high-risk categories. A treatment algorithm is presented in
a common pathogenesis.31 Figure 3 based on a provider consensus statement a vailable

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 KASI ET AL

lgM MGUS (<10%

Hemoglobin <11 g/dL
lymphoplasmacytic Bulky disease
or symptomatic
infiltration) Profound cytopenias
Platelets <120 109/L
Asymptomatic/smoldering Hemoglobin 10 g/dL
WM Neuropathy (lgM-related) Platelets <100 109/L
Hemoglobin 11 g/dL WM-associated hemolytic Hyperviscosity symptoms
anemia
Platelets 120 109/L

Hyperviscosity?

Yes No

Plasmapheresis

Single agent
rituximab* Dexamethasone +
Observation rituximab +
(1 cycle; no maintenance therapy)
*plasmapheresis if hyperviscosity cyclophosphamidea
develops with treatment

Figure 3. The risk-adapted approach to management of multiple myeloma and related disorders: Mayo Stratification for
Macroglobulinemia and Risk-Adapted Therapy (mSMART).
IgM, immunoglobulin M; MGUS, monoclonal gammopathy of unknown significance; WM, Waldenstrm macroglobulinemia.
a
Bendamustine plus rituximab is an alternative.
Updated from Ansell SM et al. Mayo Clin Proc. 2010;85(9):824-33.34

through Mayo Stratification of Macroglobulinemia and Symptomatic WM, First-Line Treatment

Risk-Adapted Therapy (mSMART).34 More than two-thirds of patients are symptomatic at the
time of their diagnosis.37 For patients with symptomatic
Indications for Plasmapheresis WM, the different classes of agents used to treat WM include
The usual indications for plasma exchange used by clini- alkylating agents (eg, cyclophosphamide and chlorambucil),
cians are compatible symptoms such as oronasal bleeding nucleoside analogues (NAs; eg, cladribine and fludarabine),
with an IgM of more than 5000 mg/dL or a laboratory monoclonal antibodies (eg, rituximab and alemtuzumab),
cutoff viscosity of 3.5 or greater.35 This is more of a guide- and novel agents (eg, bortezomib, carfilzomib [Kyprolis,
line and it is important to take into account the patients Onyx], and lenalidomide [Revlimid, Celgene]). Depending
comorbidities and severity of hyperviscosity symptoms. on the clinical situation and the overall goals of treatment,
As an example, blurred vision due to retinal hemorrhage the chemotherapeutic agents and/or monoclonal antibodies
requires urgent plasma exchange to preserve vision. Some can be used singly or in combination with each other.11,38
patients may continue to be asymptomatic beyond these There are, however, very few randomized trials to help guide
cutoffs and will not require therapy. the initial choice of treatment.39,40 Table 4 outlines selected
studies using chemoimmunotherapy combination regimens
Treatment Options in patients with WM.
When comparing the studies outlined in Table 4, there
Asymptomatic WM are several things to keep in mind. First, the age of patients
Patients without any symptoms generally are followed selected for participation varies. Studies with patients whose
every 3 to 6 months with blood count and protein mea- median age is higher are likely to have lower response rates,
surements. Asymptomatic patients with smoldering WM time to progression, and overall survival compared with stud-
and a low burden of disease can be followed for years ies conducted in a younger population. A study conducted
before treatment may be warranted.36 in untreated patients would be expected to demonstrate

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 WALDENSTRM MACROGLOBULINEMIA

Bendamustine

Chlorambucil
Alkylating agents
Cyclophosphamide

Melphalan

Cladribine
Nucleoside analogues
Fludarabine

Treatment Options Bortezomib

for WM Everolimus

Ibrutinib
Novel agents
Panobinostat

Lenalidomide

Thalidomide

Alemtuzumab
Monoclonal antibodies
Rituximab

Figure 4. Classes of agents used in the treatment of Waldenstrm macroglobulinemia.

better outcomes than one in those who have received prior c ombinations such as thalidomide/rituximab,29,44 bortezo-
treatments. The median follow-up for most of these studies is mib (Velcade, Millennium Pharmaceuticals)/rituximab,
approximately 2 years; long-term follow-up often is lacking. carfilzomib/rituximab, and bendamustine (Treanda,
The true overall survival and progression-free survival there- Teva)/rituximab have shown excellent results.45-47
fore are subject to variability. Finally, many of the studies
are small phase 2 trials or retrospective cohorts, making an Considerations When Treating WM Patients With
accurate comparison between different treatments difficult. Rituximab. One risk of treating patients with rituximab-
One of the largest randomized controlled trials was based regimens is the IgM flare, also called the rituximab
reported by Leblond and colleagues in 339 patients with flare. First described by Dimopoulos and colleagues, it refers
WM.39 The trial, which compared fludarabine with chlo- to the sharp increase in the IgM levels and/or symptoms
rambucil, showed a statistically significant improvement associated with it.29,42,48 Postulated mechanisms behind
in OS in patients receiving fludarabine. The median OS the IgM flare include rituximab-induced B-cell signaling
was not reached for the fludarabine arm, and was 69.8 that may lead to a transient rise after treatment with ritux-
months (95% CI, 61.6-79.8 months) for patients receiv- imab.48 It does not reflect treatment failure and for most
ing chlorambucil; P=.014). Median PFS in the same of the patients, a decline in IgM levels is seen within the
study was noted to be 37.8 vs 27.1 months, respectively. next several months of therapy.49 In the initial case descrip-
Single-agent rituximab is well tolerated, but pro- tions, the initial paradoxical increases in serum IgM levels
duces a partial response in only 55% of patients, making and the concomitant rise in viscosity lead to clinically sig-
it inferior to multidrug combinations (Table 4).41-43 Drug nificant events, including subdural hemorrhage, worsening

Clinical Advances in Hematology & Oncology Volume 13, Issue 1 January 201561
 KASI ET AL

eadaches, and/or epistaxis.48 IgM flare is seen in more than

h responses (50%) and minor responses (23%), the overall
half of the patients treated with rituximab alone, and in up clinical benefit rate was shown to be 73% in one study.2
to 30% of patients treated with rituximab-based combina- Agents active in patients with multiple myeloma have
tion regimens.1,5,36 The reported rates are lower in some shown activity in patients with WM and have been incorpo-
of the combination regimens of rituximab with an NA.50 rated into treatment.59 The Brutons tyrosine kinase inhibitor
When using rituximab as part of a combination regimen, ibrutinib (Imbruvica, Pharmacyclics/Janssen Biotech) shows
delaying it to the second cycle or giving it at the same time activity in WM. Data presented at the 2013 annual meet-
as chemotherapy may be safer than giving it alone.51 In ing of American Society of Hematology showed a major
general, an increase in IgM levels of more than 25% during response rate of 57.1% in the relapsed/refractory setting. The
treatment may warrant consideration of plasmapheresis in drop in IgM levels as well as the improvement in hemato-
patients with IgM levels of greater than 5000mg/dL.35,44,48 logic parameters occurred rapidly.60 Novel agents offer activ-
ity and durable responses in WM with a good safety profile
Usual Time to Best Response in Patients With WM. compared with many traditional chemotherapy regimens,
Depending on the choice of agent, the usual time to reduc- making them a viable treatment option.56,61
tion in the monoclonal protein is on the order of months.13,50
There is, however, an ongoing response (best response) Side Effects of Therapies Used in WM
noted subsequently.38,45,52 Responses are seen sooner with The toxicity profiles of combination regimens and of novel
novel agents than with alkylators or purine analogues.53 agents are a consideration in the choice of treatment for
In studies using only rituximab, it often took a year to patients with WM. Side effects can be divided into short-
achieve the best response after the initial objective or minor term and long-term. Patients treated with more of the
response in 1 study and up to 17 months in another.43,54 traditional chemotherapies experience higher rates of cyto-
Similarly, the median time to best response in patients penias and myelosuppression compared with those treated
receiving the bortezomib, dexamethasone, and rituximab with monoclonal antibodies and/or novel agents.62 Patients
(BDR) combination regimen was more than 15 months.35 exposed to NAs are at slightly increased risk for developing
myelodysplastic syndromes/acute myeloid leukemias.37,40
Symptomatic WM, Relapsed/Refractory Disease NAs also may affect stem cell mobilization if ASCT is a
Relapsed and/or refractory disease confers a poorer prog- consideration. Rituximab, one of the most commonly
nosis when compared with patients with untreated WM used monoclonal antibodies, generally is well tolerated.41
(Table 4). Other treatment regimens are selected based on Patients treated with immunomodulatory agents such as
the agents that the patient has already been treated with thalidomide and lenalidomide can develop cumulative
and the patients age and comorbidities (Figure 4). Bort- worsening neuropathies and an increase in anemia.29,44
ezomib and rituximab in patients with WM5,45 produces Bortezomib can produce a high rate of peripheral neuropa-
an overall response (at least a partial response) in 65% of thy1,5; carfilzomib has a much lower incidence of peripheral
untreated patients and 51% of treated patients. Responses neuropathy.47 Usage of the proteasome inhibitors in com-
often are not durable.5,45 In patients treated with ritux- bination regimens is associated with a high incidence of
imab, the 5-year overall response rate has been noted to herpes zoster, warranting antiviral prophylaxis.35
be 85% in untreated patients vs 48% in previously treated The mTOR inhibitor everolimus has metabolic side
patients.54 Exposure of patients to NAs should be avoided effects, resulting in elevations of triglycerides and blood sugar.
in patients who may be considered candidates for autolo- This does not require dose reduction for most patients. Lung
gous stem cell transplantation (ASCT), given problems toxicity with everolimus is rarely life-threatening, and gener-
with stem cell mobilization.36,37,55 ally manifests as an immune-mediated noninfectious pneu-
monitis.63 Patients may be asymptomatic or present with a
Novel Targeted Therapies and Regimens dry cough. Imaging studies, including a CT scan, demon-
Over the past decade, numerous novel agents have been iden- strate ground-glass opacities requiring discontinuation of the
tified that have shown activity in patients with WM (Table drug. Corticosteroids are used in treating this pneumonitis
4). The studies have demonstrated high levels of activity in after infectious causes of lung toxicity are ruled out.
both untreated patients and patients with relapsed/refrac-
tory WM.56,57 As noted in Table 4, the response rate varies Role of Stem Cell Transplantation
from 20% to 70% for most of the novel targeted therapies There are a limited number of studies addressing the ques-
used as single agents.56 The higher responses seen are in the tion of autologous stem cell transplantation in patients with
untreated WM setting.1,54,58 Everolimus, a mammalian target WM (Table 4).37,52,64,65 A review article published in 2012
of rapamycin (mTOR) inhibitor, shows significant activ- examined data on the safety and efficacy of autologous stem
ity in patients with relapsed WM.2 Counting both p artial cell transplantation and durability of responses.64 Autologous

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 WALDENSTRM MACROGLOBULINEMIA

Table 4. Studies of Treatment Regimens and Novel Agents Used in the Treatment of Waldenstrm Macroglobulinemia
Author Treatment N Median Setting ORRa PFS OS
Age, y
Cytotoxic chemotherapy regimens
Treon,35 Bortezomib/dexametha- 23 66 Untreated 83% NR NR
2009 sone/rituximab Exceeds 30 mo
Dimopou- Bortezomib/dexametha- 59 70 Untreated 70% 42 mo 82% 3-y survival
los,1 2013 sone/rituximab
Treon,47 Carfilzomib/rituximab/ 31 61 90.3% untreated 87.1% NR No deaths
2014 dexamethasone reported
Tedeschi,50 Fludarabine/cyclophos- 43 65 65% untreated 74.4% 69.1% at 4 y
2011 phamide/rituximab
Dimopou- Dexamethasone/ritux- 72 69 Untreated 74% 2-y PFS 67% 78% 2-y survival
los,36 2007 imab/cyclophosphamide
Dimopou- Fludarabine/ 11 73 18% untreated 55% TTP 24 mo 70% 2-y survival
los53 cyclophosphamide 2 (18%) relapses
7 (64%) refractory
Leblond,39,c Fludarabine 167 68 Untreated 45.6% 37.8 mo NR
2013 vs vs vs vs vs
chlorambucil 165 35.9% 27.1 mo 69.8 mo
Leblond,40,c Fludarabine 45 64 Relapsed/refractory 30% 19 mo 41 mo
2001 vs vs 50 (54%) relapses vs vs vs
cyclophosphamide/ 45 42 (46%) refractory 11% 3 mo 45 mo
doxorubicin/prednisone
Dhodapkar13 Fludarabine 182 33% 64.8% untreated 36% 5-y PFS 41% Estimated OS at 5
>70 y y was 58%
Hellmann,62 Cladribine 22 62 41% untreated 40.9%
1999 Mean duration 7 deaths reported;
of response 12 mean OS 36 mo
mo
Liu67 Cladribine 20 66 57% untreated 55% 86% at 4 y
1 relapse in
responders at
18 mo
Rituximab-based doublet combination therapies
Treon,51 Fludarabine/rituximab 43 61 63% untreated 86% TTP 51.2 mo
2009 2 deaths reported
Laszlo,4 Cladribine/rituximab 29 55.1% untreated 79.3% NR NR
2011 4 relapses at 50
mo
Treon,46 Bendamustine/ 30 68 Relapsed/refractory 83.3% TTP 13.2 mo
2011 rituximab Relapsed, 47% 1 reported death
Refractory, 53% due to transfor-
mation
Ghobrial,5 Bortezomib/rituximab 26 63 Untreated 65% NR NR
2010 6 pt progressed Estimated 1-y OS
at 14 mo of 96%
Ghobrial,45 Bortezomib/rituximab 37 64 Relapsed/refractory 51% 15.6 mo NR
2010 >1 therapies (70%) (18 pt Estimated 1-y OS
progressed at of 94%
16 mo)
Treon,29 Thalidomide/rituximab 25 62 80% untreated 64% TTP 34.8 mo
2008 2 unrelated deaths

Clinical Advances in Hematology & Oncology Volume 13, Issue 1 January 201563
 KASI ET AL

Treon,44,b Lenalidomide/rituximab 16 65 75% untreated 25% TTP 17.1 mo

2009
Single-agent rituximab
Dimopou- Rituximab 27 72 56% untreated 44% TTP 16 mo
los,42 2002
Treon,43 Rituximab 29 65 42% untreated 48.3% TTP 14 mo
2005 3 (10%) relapses 1 unrelated death
14 (48%) refractory
Gertz,54 Rituximab 69 66 49.2% untreated 32% 23.1 mo 66% at 5 y
2009
Novel single agents
Ghobrial,2 Everolimus 60 64 Relapsed 50% 21 mo NR
2014
Treon,58 Alemtuzumab 28 59.5 17% untreated 36% TTP 14.5 mo
2011 11 (36%) relapses 4 deaths reported
12 (43%) refractory
Treon,66 Bortezomib 27 62 Relapsed/refractory 48.1% TTP 6.6 mo
2007 12 (44%) relapses 1 death reported
15 (56%) refractory
Chen61 Bortezomib 27 65 44% untreated 44% 16.3 mo
Treon,60 Ibrutinib 63 63 Relapsed/refractory 57.1%
2013 46 (73%) relapses
17 (27%) refractory
Ghobrial,56 Panobinostat 36 62 Relapsed/refractory 22% 6.6 mo
2013
Ghobrial,68 Perifosine 37 65 >1 therapies (68%) 11% 12.6 mo 26 mo
2010
Dimopou- Thalidomide 20 72 50% untreated 25% TTP 4 mo
los,59 2001 2 deaths reported
Select studies on ASCT and AlloSCT
Kyriakou,37 ASCT 155 53 <3 therapies 68% 89% 61.7% at 3 y Estimated OS at 5
2010 3 therapies 32% 39.7% at 5 y y was 77%

Garnier52 AlloSCT 24 48 Median of 3 lines of 91% 58% at 5 y Estimated OS at 5

therapy y was 67%
Dreger69 26 AlloSCT 36 49 3 therapies 58%d 31% at 3 y 46% at 3 y
10 ASCT 56 52.7% 65% at 3 y 70% at 3 y
AlloSCT, allogeneic stem cell transplantation; ASCT, autologous stem cell transplantation; mo, months; NR, not reached; ORR, overall response rate; OS, overall
survival; PFS, progression-free survival; pts, patients; TTP, time to progression; y, year/years.
a
Partial response or better.
b
Discontinuation of lenalidomide occurred in 14 of the 16 patients owing to worsening anemia in these patients, which led to the study being stopped.
c
Randomized controlled trial.
d
10 (28%) patients died prior to day 100 after transplant; their responses therefore could not be assessed.

stem cell transplantation is a viable option in patients at the Monitoring

time of relapse if they retain chemotherapy sensitivity. The Patients with WM are followed every 3 to 6 months,
target population would generally be young patients at early with blood work as shown in Table 3 and scans if needed.
relapse.37,64 Stem cell transplantation also is a viable treatment Patients may have discordant responses between the IgM
consideration for countries where not all novel treatments level and the degree of marrow infiltration.66 Because the
may be available. The use of allogeneic stem cell transplanta- markers in WM are generally surrogates of the disease
tion should be limited to clinical trial settings.64 burden, repeat bone marrow biopsies are not needed.

64Clinical Advances in Hematology & Oncology Volume 13, Issue 1 January 2015
 WALDENSTRM MACROGLOBULINEMIA

The Road Ahead MYD88 and CXCR4 are determinants of clinical presentation and overall survival
in Waldenstrom macroglobulinemia. Blood. 2014;123(18):2791-2796.
19. Cao Y, Hunter ZR, Liu X, et al. The WHIM-like CXCR4(S338X) somatic
mutation activates AKT and ERK, and promotes resistance to ibrutinib and other
Studies suggest that combining novel agents, such as histone
agents used in the treatment of Waldenstroms Macroglobulinemia [published
deacetylase inhibitors and proteasome inhibitors, holds online June 10, 2014]. Leukemia. doi:10.1038/leu.2014.187.
promise in multiple myeloma.47,56 The data on everolimus, 20. Treon SP, Hunter ZR, Castillo JJ, Merlini G. Waldenstrm macroglobulin-
emia. Hematol Oncol Clin North Am. 2014;28(5):945-970.
including its long-term tolerability, make it a reasonable
21. Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom
new treatment option for WM.2 Newer biological insights macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like
into MYD88 and WHIM-like CXCR4 have been signifi- CXCR4 mutations, and small somatic deletions associated with B-cell lymphoma-
genesis. Blood. 2014;123(11):1637-1646.
cant and intriguing not just in terms of their diagnostic and
22. Ondrejka SL, Lin JJ, Warden DW, Durkin L, Cook JR, Hsi ED. MYD88 L265P
prognostic value, but also as potential targets for therapy in somatic mutation: its usefulness in the differential diagnosis of bone marrow involve-
patients with WM. ment by B-cell lymphoproliferative disorders. Am J Clin Pathol. 2013;140(3):387-394.
23. Lenz G. Waldenstrom macroglobulinemia: genetics dictates clinical course.
Blood. 2014;123(18):2750-2751.
Disclosures 24. Nguyen-Khac F, Lambert J, Chapiro E, et al; Groupe Franais dEtude de
Drs Kasi and Ansell have reported no relevant financial rela- la Leucmie Lymphode Chronique et Maladie de Waldenstrm (GFCLL/MW);
Groupe Ouest-Est dtude des Leucmie Aigus et Autres Maladies du Sang
tionships. Dr Gertz has disclosed financial relationships with
(GOELAMS); Groupe dEtude des Lymphomes de lAdulte (GELA). Chromo-
Onyx, Celgene, Novartis, and Millennium. somal aberrations and their prognostic value in a series of 174 untreated patients
with Waldenstrms macroglobulinemia. Haematologica. 2013;98(4):649-654.
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