Everolimus, an mTOR inhibitor, perifosine, an AKT inhibitor, enzastaurin, a phosphatidylinositide3 kinase/AKT inhibitor, panobinostat, a histone deacetylase inhibitor, ofatumumab, a third-generation anti-CD20 monoclonal antibody, and ibrutinib, a Bruton tyrosinekinase inhibitor, and newer drugs from known active subclasses, such as pomalidomide (immunomodulatory) and carfilzomib (proteasome inhibitor) arepromising drugs in various stages of study in WM. They may expand future treatment options.
WM is defined by WHO as a lymphoplasmacytic lymphoma associated with a monoclonal IgM protein (regardless of its size) and bone marrow infiltration by clonal LPC cells . Median age at diagnosis is70 years with male predominance the incidence is lower in non-Caucasians . It accounts for 1%-2% of hematological neoplasms . There is personal or family history of autoimmune, inflammatory and infective disorders particularly Sjogren syndrome and autoimmune hemolytic anemia. There is increased risk of WM and other B-cell disorders amongst relatives of patients with WM .
IgM-MGUS is characterized by the presence of an IgM monoclonal protein, less than 10% clonal lymphoplasmacytic bone marrow cells, and no symptoms attributable to tumor mass or infiltrations . It is a precursor state for WM. Approximately 2% of IgM MGUS patients evolve to a B-cell malignancy per year, with most of these individuals progressing to WM . Smoldering WM is characterized by an IgM monoclonal protein, clonal lymphoplasmacytic bone marrow infiltration greater than 10%, no symptoms attributable to tumor mass or infiltration, and no IgM-mediated symptoms . Clinical features are related to disease burden, such as cytopenias, organomegaly and constitutional symptoms, or to IgM paraprotein such as hyper viscosity syndrome, hemolytic anemia, immune complex vasculitis and amyloidosis or to autoantibody specificity suchas
peripheral neuropathy, cold hemagglutinin disease and acquired von Willebrand disease .
Bing Neel syndrome (rare) presents usually at WM relapse or at first diagnosis. Symptoms are diverse, non-specific and gradually progressive over weeks to months. They reflect LPC involvement of the CNS and rarely the peripheral nervous system. LPC may be detected in the cerebrospinal fluid, the meninges and/or the cerebral parenchyma . WM patients are at increased risk for second malignancies, including transformation to DLBCL (5-10%), myelodysplastic syndrome, acute myeloid leukemia and solid cancers . Development of bulky rapidly enlarging lymph node masses, extranodal disease and marked elevation in serum lactate dehydrogenase are suggestive of transformation to DLBCL . The genomic landscape of WM is characterized by highly recurring MYD88 (>90% of cases) resulting in a protein change from leucine to proline at amino acid position 265 .
In tumor cells, MYD88L265P triggers activation of NF-κB through BTK or IRAK (IRAK1 and IRAK4) pathways. MYD88L265P was present in 50% to 80% of IgM MGUS, suggesting an early oncogenic event for this mutation . MYD88 mutation is not unique to WM. It distinguished WM from overlapping entities such as marginal zone lymphoma, chronic lymphocytic leukemia, and multiple myeloma, wherein MYD88L265P was either absent or infrequently observed (10%) . CXCR4 is mutated in 30% of WM patients. CXCR4 stimulation by its ligand CXCL12 activates AKT1 and mitogen-activated protein kinase family signaling, as well as facilitates cell migration and homing in WM cells . The prolonged activation of CXCR4 signaling due to WHIM mutations may exaggerate these effects. Polymorphisms of CXCR4 ligand
and CXCL12 have been associated with poor post treatment
clinical outcomes .
MYD88 and CXCR4 mutation divide WM into three
genomic groups (MYD88L265P CXCR4WT, MYD88L265P
CXCR4WHIM, and MYD88WTCXCR4WT) on the basis of clinical
manifestations and survival . Other major pathway was the
loss of chromatin remodeling proteins, ARID1A and ARID1B.
ARID1Awas the third most common single nucleotide variant
target in WM, they are thought to exert their effects via p53 and
CDKN1A regulation . BCR-signaling-associated mutations
occur less frequently (15% of WM cases), and are restricted
to the CD79A and CD79B genes . Epigenetic dysregulation,
aberrations in the phosphatidylinositol 3-kinase/mTOR, NFκB,
JAK/STAT signaling pathways, as well as bone marrow micro
environmental interactions, may be other key factors involved in
WM pathogenesis .
Bone marrow aspirate and trephine biopsies should
be obtained and supplemented by flow cytometric and
immunohistochemistry studies . The bone marrow pattern
is predominantly intertrabecular . The immuno-phenotype
of WM consists of expression of pan-B-cell markers (CD19,
CD20, CD22), cytoplasmic immunoglobulin (cIg), FMC7, CD38,
and CD79aand typically negative for CD3 and CD103 .
The plasma cells number is generally in the normal range, but
they differ from normal and myeloma cells by being positive for
CD38, and commonly express CD19, CD45, and CD20, but lack
IgM levels by densitometry or total serum IgM quantitation
by nephelometry must be determined. IgM values assessed by
nephelometry are higher than M protein values determined by
densitometry that is why sequential response assessments for
individual patients must be carried with the same methodology
. Quantification of serum viscosity might be helpful .
Hyperviscosity syndrome is evident when IgM M-protein >40
g/l and/or  the serum viscosity exceeds 4 centipoise. Serum
viscosity does not always correspond to the clinical severity of
hyperviscosity. Venous engorgement ‘sausaging’ in the retinal
veins by fundoscopy is an excellent indicator of clinically
relevant hyperviscosity .
Evaluation of anti-myelin associated glycoprotein,
antigangliosides M1 and anti-sulfatide IgM antibodies may
support the diagnosis of IgM-related neuropathy. Also, the
possibility of amyloid light-chain amyloidosis in association with
peripheral neuropathy needs to be considered . Screening for
hepatitis B and C viruses is required prior to the introduction
of rituximab-containing treatments . An ultrasound or
CT scan should be carried out to documentorganomegaly/
adenopathies. PET scanning is indicated when a large cell lymphoma transformation is suspected . Testing for MYD88
is essential for patient’s candidates for ibrutinib therapy .
Cytogenetic analysis is not required for the routine diagnostic
assessment of WM . Partial or whole 6q deletion is the most
common recurrent chromosomal abnormality (approximately
50% of patients) and was associated with a complex karyotype,
hypoalbuminemia, high 2-microglobulin levels  and an
adverse prognosis .
Other cytogenetic aberrations, include trisomy 18 (15%) and
13q14 deletion (13%). Less than 10% of patients had trisomy
4, 17p13 (TP53) deletion, 11q22 (ATM) deletion, trisomy 12, or
14q32 (IGH) translocations. Deletion of 6q, 11q and trisomy 4
had adverse effects on survival. Recurrent deletions on 13q14
and 17p13 have been mostly seen in more advanced stages of the
disease . Although not unique to WM, inactivating mutations
of TRAF3 (located on cytoband 14q32.32) lead to constitutive
activation of NF-κB pathways and are recurrent findings in a
small percentage (~5%) of WM patients .
In International Prognostic Scoring System for WM I
(IPSSWM), 5 covariates (age > 65 years, hemoglobin ≤11.5 g/
dL, platelet counts ≤100x109/L, 2-microglobulin>3mg/L,
serum monoclonal protein >70 g/L) defined 3 risk groups
(low, intermediate and high risk respectively) . The risk
category is designated as low (zero or 1 risk factor, except age),
intermediate (age older than 65 years or 2 risk factors), or high
(>2 risk factors) . These three risk categories are associated
with 5-year survival rates of 87%, 68% and 36% respectively
. Lactate dehydrogenase level may have a role in separating
the high-risk patients into two distinct categories . IPSSWM
risk category is used for risk stratification in randomized clinical
Close observation is recommended for patients who do not
fulfill the criteria for WM, and for whom laboratory evidence is
the only indicator of disease progression (eg, a minor decrease in
hemoglobin level with asymptomatic anemia or mild increases
in IgM) or mild increase of lymphadenopathy or splenomegaly
without patient discomfort . They can be safely observed at
3-6 monthly intervals. The risk of progression to symptomatic
disease is 59% at 5 years . Criteria for initiation of therapy
is IgM-related complications and/orsymptoms related to direct
BM involvement by tumor cells such ascytopenias, constitutional
symptoms and bulky extramedullary disease .
Urgent therapy is needed insymptomatic hyperviscosity,
moderate to severe hemolytic anemia and symptomatic
cryoglobulinemia . Plasma exchange may be warranted
in asymptomatic individuals, such as those with multiple
vascular co-morbidities and in patients with a high plasma
viscosity >4cP prior to red cells transfusion . Management
of symptomatic, untreated WM patients Rituximab aloneis
considered inperipheral neuropathy related to the IgM antimyelin-associated glycoprotein activity  or in frail patients
who are less likely to tolerate chemoimmunotherapy .
The combination of rituximab with chemotherapy is the
first option in medically fit patients particularly, when rapid
response is needed  because rituximab is an active non
myelosuppressive agent . Response rate of 70-90% have
been reported in rituximab based combination . The choice
of chemotherapy depends on comorbidities, how fast disease
control is required, and the manifestations of the disease
. R-CHOP is no longer considered a first-line choice ,
Dexamethasone, rituximab, and cyclophosphamide (DRC) is a
primary choice in frail patients requiring combination therapy.
Toxicities were mild, with only 9% of patients having grade 3 to
4 neutropenia .
Bendamustine-rituximab (BR) is effective in patients with
high tumor bulk . Bortezomib-rituximab combination may
be considered in patients with specific high-risk features (i.e.,
high IgM levels, symptomatic hyperviscosity, cryoglobulinemia
or cold agglutinemia, amyloidosis and renal impairment) or
in younger patients to avoid use of alkylator or nucleoside
analogtherapy . Bortezomib should ideally be given once per
week and possibly by a subcutaneous route. For urgent reduction
of the IgM level, bortezomib can be started at twice-per-week
doses for 1 or 2 cycles and then be changed to once-per-week
dosing to reduce risk of neurotoxicity . Bortezomib is not
toxic to stem cells . Rituximab plus carfilzomib are mainly
used as an emerging neuropathy-sparing option. No grade
≥3 neuropathy was observed . Single agent chlorambucil
may still be suitable therapy for very frail patients in whom
combination therapy is considered inappropriate .
CR: Absence of serum monoclonal IgM protein
by immunofixation, normal serum IgM level, complete
resolution of extramedullary disease, i.e., lymphadenopathy
and splenomegaly if present at baseline, morphologically
normal bone marrow aspirate and trephine biopsy.
VGPR: Monoclonal IgM protein is detectable, ≥90%
reduction in serum IgM level from baseline, complete
resolution of extramedullary disease, ie, lymphadenopathy/
splenomegaly if present at baseline, no new signs or
symptoms of active disease.
Partial response: monoclonal IgM protein is detectable
≥50% but 90% reduction in serum IgM level from baseline,
reduction in extramedullary disease, i.e., lymphadenopathy/
splenomegaly if present at baseline, No new signs or
symptoms of active disease.
Minor response: monoclonal IgM protein is detectable
≥25% but 50% reduction in serum IgM level from baseline,
no new signs or symptoms of active disease.
Stable disease: monoclonal IgM protein is detectable
25% reduction and ession in extramedullary disease, i.e.,
lymphadenopathy/splenomegaly, no new signs or symptoms
of active disease.
Progressive disease: ≥25% increase in serum IgM
level (an absolute increase of 5 g/L (0.5 g/dL) from lowest
nadir (requires confirmation) and/or progression in clinical
features attributable the disease .
Maintenance rituximab is recommended by NCCN for
patients in CR for initial therapy or asymptomatic patients
achieved very good, partial or minor response . Maintenance
rituximab increased incidence of grades 1 and 2 sinobronchial
infections along with reduction of uninvolved immunoglobulins
(IgA and IgG). It appeared to extend PFS and OS in comparison
with observation . Management of symptomatic previously
treated WM patients. Re-treatment with prior regimen used for
symptomatic, untreated patients may be considered if a response
was achieved for 2 or more years with the priorregimen .
Repeat bone marrow aspirate and trephine assessment and CT
scanning prior to the reintroduction of treatment .
BR is well tolerated in relapsed/refractory disease. Prolonged
myelosuppression occurred in patients who had received prior
nucleoside analog therapy . Of atumumabis a fully human
monoclonal antibody (IgG1) that targets a CD20 region at a
different epitope than that of rituximab. It may represent a
potential therapeutic option in rituximab in tolerant patients.
A therapeutic test dose with appropriate prophylaxis should
be considered before of atumumab administration. There is a
risk of IgM flare as with rituximab . Rituximab with purine
analogs (rituximab and fludarabine / rituximab, fludarabine,
and cyclophosphamide) remain an option for patients with highrisk
of relapsing disease and adequate performance status. They
have a median PFS exceeding 50 months. In patients who may
be candidates for single agent oral therapy, oral fludarabine (if
available) is recommended over chlorambucil .
Immunomodulatory agents:Given the potential adverse
events of lenalidomide and pomalidomide, their use should be
considered in the context of a clinical trial . Ibrutinib is an
orally administered, irreversible inhibitor of BTK. It represents
a novel and effective treatment option for both treatment naive
and relapsing patients not candidates for chemoimmunotherapy
. Extramedullary disease was affected by ibrutinib therapy
. It prevents binding of MYD88 to BTK in L256P cells .
Ibrutinib showed rapid response kinetics, with a median time
to response of 4 weeks . The response was highest among
patients with MYD88L265Pand those with absent CXCR4
The incidence of ibrutinib-triggered peripheral lymphocytosis
was higher among patients with MYD88L265PCXCR4WT than
among patients with MYD88L265PCXCR4WHIM . Overall
treatment with ibrutinib is well tolerated in WM patients .
Patients who progressed on first-line ibrutinib should not be
retreated with ibrutinib . A potential off-target effect is
atrial fibrillation (5%) in patients with history of arrhythmia
. Ibrutinib produces a mild decrease in QT interval of
unknown underlying mechanism and safety relevance . The
mammalian target of rapamycin (mTOR) inhibitor (everolimus)
owing to the toxicities (hematologic, mouth sores and pulmonary
pneumonitis) associated with everolimus, this agent is best
considered in patients who are unresponsive or progressed
after multiple lines of other better-tolerated therapies .
Discordance between serum IgM level and bone marrow disease
response is commonand complicates response assessment .
CXCR4 antagonist (plerixafor):The feasibility of longterm
use of plerixa for has been reported in patients with
WHIM syndrome. It sensitizes engineered WM cells to express
CXCR4WHIM receptors to undergo apoptosis in response to
ibrutinib. Clinical trials of other CXCR4 inhibitors are ongoing
. The Akt inhibitor perifosine has shown a response rate of
35% but is associated with high levels of gastrointestinal toxicity.
Histone deacetylase inhibitor panobinostat as a single agent has
resulted in a minimal response or better in 47%. The median
progression-free survival was 6.6 months . MYD88 peptide
inhibitor, MYD88L265P-directed immune activation and CD19
directed chimeric antigen receptor T cell therapy are 3 highly
innovative WM specific therapies .
Avoid continuous oral alkylator cyclophosphamide,
chlorambucil and bendamustine or nucleoside analogue
(cladribine and fludarabine) therapy if SCT is considered
Patients receiving purine analogues, alemtuzumab and
bendamustine should receive irradiated blood products for
Serum IgM can spike (IgM flare) during rituximabbased
therapy (or other anti-CD20 monoclonal antibodies)
for several weeks or months independent of tumor cell
killing. This does not imply disease progression, in most
cases; it will resolve . On the other hand, bortezomib or
everolimus can suppress IgM level .
Rituximab should be avoided or withheld during the
first 1 or 2 courses of systemic therapy until IgM levels
decrease to a safer level, or plasmapheresis should be
performed before giving rituximab to patients with high IgM
levels (typically >4000 mg/dL)  because IgM flare could
prompt symptomatic hyperviscosity.
LON has been described with rituximab, mostly when
it is combined with chemotherapy. An association between
a specific polymorphism in the IgG Fc receptor (FcgRIIIa-
V158F) and LON has been described .
Best response to alkylators , purine analogue and
monoclonal antibody therapy, may not be achieved until 6
months after treatment. These agents selectively deplete
CD20+ B-cell component with sparing of the CD138+ plasma
cell component of the disease. There is significant B-cell
depletion in the marrow but suboptimal IgM responses
Satisfactory IgM responses may be achieved after
many months into treatment. Bone marrow assessment is
recommended to assess response. Conversely, bortezomibcontaining
regimens may demonstrate excellent IgM
responses but suboptimal bone marrow responses .
Prophylaxis against herpes zoster is strongly
recommended for WM patients receiving proteasome
Vaccinations should be avoided, if possible, 2
weeks prior to, during and for 6 months after chemoimmunotherapy
Transient increases in serum IgM levels commonly
occur when ibrutinib was withheld because of toxic effects
or procedures. These levels decreased with reinstitution of
An off-target effect of ibrutinib on platelet aggregation
has been described in CLL trials. Care should be taken if
anticoagulant therapy or drugs that inhibit platelet function
is used. Test for von Willebrand activity in patients with a
history of bleeding diathesis. In case of surgery, ibrutinib
should be held at least 3 to 7 days pre- and post surgery,
depending upon the type of surgery and the risk of bleeding
Treatment-associated morbidity:Prolonged risk of
secondary infections with monoclonal antibodies and purine
analogues, risk of long-lasting cytopenias, myelodysplasia and
secondary malignancies from fludarabine, and worsening of
peripheral neuropathy related to bortezomib . Grade 2 or
greater neutropenia and thrombocytopenia may occur with
ibrutinib in heavily pretreated patients .
Stem cell collection should be performed pre-emptively after
patients achieve first remission. ASCT is an effective treatment
option for eligible patients up to 75 years. It is recommended
in high risk WM with elevated lactate dehydrogenase indicating
a high tumor burden. It should ideally be offered at early
relapses . Chemosensitivity at the time of transplant is
the most important predictor of response . ASCT is not as
beneficial for patients exposed to more than 3 lines of therapy or with chemotherapy refractory disease. Allogeneic SCT, when
appropriate, should preferably be considered investigational
due to high non relapse mortality .
Follow-up should include history, physical examination,
blood count, routine chemistry and quantification of IgM every
3 months for 2 years, every 4-6 months for an additional 3
years, and subsequently once a year with special attention
to transformation and secondary malignancies, including
secondary leukemia. Radiological or ultrasound examinations
every 6 months for 2 years are recommended, and annually
thereafter only in cases of initial splenomegaly or lymph node
enlargement. Regular CT scans are not necessary outside clinical
Trials with ibrutinib and other BCR inhibitors are needed
to assess their efficacy and tolerability in treatment-naive
patients. BCR inhibitors combined with proteasome inhibitors
in relapsed/refractory setting would be of interest to overcome
resistance by interfering with the 2 key pathways that are affected
by MYD88. Combination of CXCR4 antagonists with ibrutinib in
patients with CXCR4WHIM mutation as well as Obinutuzumab,
as a combination partner in WM are of interest .