WALDENSTRÖM’s MACROGLOBULINAEMIA
According to the international consensus panel recommendations Waldenstr Öm’s
macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder
(lymphoplasmacytoid lymphoma) characterised primarily by bone marrow infiltration
with a predominantly intertrabecular pattern together with a demonstrable IgM
paraprotein (Dimopoulos et al., 2008).
Diagnosis of a lymphoplasmacytic lymphoma
This should be based on the intertrabecullar infiltration of the bone marrow by
lymphoplasmacytoid lymphoma. The characteristic cells are small lymphocytes with
evidence of plasmacytoid/ plasma cell differentiation. Lymph node biopsy should also
be encouraged if feasible. Clinical, morphological and immunophenotypic features of
other low grade LPD should be excluded. In cases presenting exclusively with
extramedullary disease it is important to exclude other LPD especially MZL.
An additional characteristic but not diagnostic feature of WM is that there is an
increase in mast cells in the bone marrow biopsy.
Immunophenotype of WM:
The characteristic phenotype includes:
Pan-B cell antigens: CD19, CD20, CD22 and CD79a and CD79b
Others often expressed: CD5, CD27, FMC 7, BCL-2 and CD52
Rarely expressed: CD25 (This does not exclude the diagnosis but care should be
taken to exclude CLL and MZL)
CD103 and CD138 are also rarely expressed*
* It is not clear from published studies whether this refers to the lymphocytes or
plasma cells. There is often a distinct population of CD 138+ plasma cells in WM and
they usually have plasmacytic morphology (personal observation).
It may be necessary to ask for Cyclin D-1 to exclude MCL in those who are CD 5 +ive
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Distinction between asymptomatic WM, symptomatic WM, MGUS and other IgM
related disorders
There are four subtypes of LPL with IgM paraproteinaemias that are proposed by the
workshop. These are:




Asymptomatic Waldenström’s macroglobulinaemia. These patients have a
clear infiltration by LPL, an IgM paraprotein of any level but without symptoms
either attributable to BM infiltration or to the IgM paraprotein.
Symptomatic WM: These patients have a clear infiltration by LPL, an IgM
paraprotein of any level and symptoms either attributable to BM infiltration,
organomegaly, constitutional symptoms or to the IgM paraprotein
(hyperviscosity, neuropathy, cold agglutinins, amyloidosis or
cryoglobulinaemia).
IgM MGUS: Those with an IgM paraprotein but without demonstrable
confirmed BM infiltration by LPL. The level of PP is not important but is rarely
above 30g/L.
Other IgM related disorders: this is a proposed category that includes patients
with an IgM paraprotein but without a demonstrable LPL, and who have
symptoms attributable to the paraproteinaemia. These include symptomatic
autoimmune phenomena, neuropathy, cold agglutinins, amyloidosis or
cryoglobulinaemia.
Differential diagnosis of other lymphoproliferative disorders secreting IgM
1. IgM myeloma: the morphology of the bone marrow infiltrate is predomiantly
plasmacytic and there are lytic lesions.
2. Splenic marginal zone lymphoma (SMZL): strong expression of CD 22 and
CD11c. CD25 more commonly expressed in WM. Cytogenetics: 7q-, +3q and
+5 in SMZL
3. Mantle cell lymphoma: cells have irregular nuclei, involvement of lymph nodes
and extranodal sites and spleen. T(11;14) ( q13;q32)
4. B CLL: morphology of cells. Expression of CD5 and CD23
Cytogenetics
The deletions of the long arm of chromosome 6 (6q deletions) is the only recurrent
abnormality found in approximately 50% of cases. No illegitimate recombinations of
the heavy chain locus on chromosome 14 have been found.
Investigations at outset:
Laboratory tests
 FBC blood film and reticulocytes
 LFT, creatinine and electrolytes
 Immunoglobulin quantitation
 Paraprotein quantitation
 BJP
 Serum free light chains
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
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
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Beta 2 microglobulin
Consider Cryoglobulins
Direct antiglobulin test
Antibody screen
In case of neuropathy anti MAG antibodies. Consider anti ganglioside and
sulphatides.
Consider plasma viscosity if there is clinical suspicion of hyperviscosity
Other tests
 Imaging: CT scan of chest and abdomen is only needed as a baseline before
treatment or only if it will influence decision to treat.
 Nerve conduction studies in cases of neuropathy.
Prognostic factors:
The median survival of patients with WM is 5 years but 20% of patients survive more
than 10 years and 10-20% may die of unrelated caused.
There are few studies that have defined the prognostic factors in WM. The most
relevant prognostic factors affecting survival beta 2 microglobulin, Hb, Albumin and
age. With these simple parameters, patients were stratified into three groups at low,
intermediate and high risk of death, with 5-year survival probabilities of 92%, 63%,
and 27%, respectively. In the SWOG study, a serum beta-2 microglobulin level
higher than 3 mg/L, a hemoglobin level below 12 g/dL, and a serum IgM level above
40 g/L were significant adverse prognostic factors for survival. A staging system
using these variables identified four distinct subsets of patients with estimated 5-year
survival rates of 87%, 64%, 53%, and 12%. Response to treatment has also been
found to be associated with better survival.
The International prognostic scoring system (IPSS) for WM recognised 5 adverse
covariates. (Morel et al Blood on Line Feb 5th 2009)
 Age >65 years
 Haemoglobin ≤11.5 g/dL
 Platelet count ≤100 x109/L
 Beta2-microglobulin >3 mg/L
 Monoclonal IgM conc. >70 g/L
Category
% patients
No of factors
Low risk
27%
≤1 factor
Intermediate risk
38%
2 or age >65
High risk
35%
≥2
5 year survival
87%
68 %
36%
Initiation of therapy appropriate in patients with:
 Rising paraproteins and progressive symptoms of disease.
 Hb <10g/dL, or platelets of <100 x109/L attributable to disease
 Bulky disease or related constitutional symptoms
 Hyperviscosity
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

Evidence of disease transformation
Symptoms related to the paraprotein such as symptomatic polyneuropathy,
cold agglutinins, amyloidosis, nephropathy, autoimmune phenomena and
symptomatic cryoglobulinaemia.
Follow up of asymptomatic patients:
 Asymptomatic WM every 3-6 months
 MGUS every 6-12 months.
Recommendations for treatment (International Working Group)
There are a variety of drugs and combinations which have been used successfully for
the treatment of WM. However there are no comparative controlled trials of any
therapy against others and this will therefore be reflected in the levels of
recommendations.
The table below taken from Dimopoulous et al 2008 (J Clin Oncol. 27:120-126) sets
out the treatment options for first line therapy and the level of evidence and
recommendation.
The choice of therapy should take into account the individual patient’s circumstances.
For example it is advisable to avoid using alkylating agents and probably also
nucleoside analogues in younger patients in whom PBSCT may be considered as
these drugs may reduce the ability to harvest PBSC. Another consideration is the
leukaemogenic potential of these drugs in younger patients.
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Recommendations from the international expert panel are that autologous autografts
may be used in younger patients after relapse. It is also recommended that
allogeneic transplants should only be considered in the context of clinical trials.
Addition of rituximab to other agents may produce a more complete and quicker
response. However a ‘flare’ reaction may occur whereby there is an increase of
paraprotein prior to its reduction.
Special conditions:
Salvage/ Relapse Therapy
The choice of salvage therapy depends on the first-line treatment used, the quality
and duration of response, and other variables such as age, tolerance of initial
therapy, and suitability for stem-cell transplantation.
If the original response was prolonged to more than 12 months unmaintained, the
initially effective treatment should be considered if well tolerated.
If relapse occurred in a shorter period of time, use of an alternate single agent or
combination is recommended. For patients who have short remissions or resistance
to a first-line regimen, second-line treatment may include agents of a different class
either alone or in combination. In that setting, the R-FC regimen may be appropriate,
although it should be avoided in younger patients and patients who are eligible for
ASCT in whom stem cells have not previously been collected and stored.
Bortezomib-based therapy may also be an appropriate second-line choice.
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In view of recent data on the activity of alemtuzumab in pretreated patients, this
agent may represent a reasonable third-line therapy.
The place of high-dose therapy with ASCT or alloSCT requires further evaluation in
the context of prospective trials, which should focus primarily on patients with highrisk disease or on an individual basis in selected young patients with high risk
disease.
Based on the International Working Group recommendations the following
protocols are recommended within NWLCN:
Protocols:
2.01
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2.03
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Chlorambucil
Suitable for elderly patients
Caution with frail patients and renal impairment
Rituximab
Suitable for frail patients and patients with co-morbidities
Caution in patients with high paraprotein levels
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2.05
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Fludarabine
Suitable for younger or fitter patients
Caution: can produce prolonged cytopenias
2.27
Rituximab-Fludarabine
2.06
Fludarabine - Cyclophosphamide
6.01
R-FC
6.02
DRC
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2.07
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Transplantation candidate: cytopenias and high M-protein
Non-transplantation candidate: cytopenias
R-CHOP
Transplantation candidate: high M-protein or
Non-transplantation candidate: cytopenias only
2.24
R-CVP
3.10
Thalidomide ± Dexamethasone
6.03
R-Thalidomide

Patients with cytopenias, transplant or non-transplant candidates
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Summary of updated response criteria from the 3rd International Workshop on
Waldenstöm’s Macroglobulinemia
Response
Complete
response
(CR)
Partial
response
(PR)
Stable
disease
(SD)
Criteria
Disappearance of monoclonal protein by immunofixation; no histologic evidence
of bone marrow involvement, resolution of any adenopathy/
organomegaly (confirmed by CT scan), or signs or symptoms attributable to
WM. Reconfirmation of the CR status is required at least 6
weeks apart with a second immunofixation.
At least 50% reduction of serum monoclonal IgM concentration on protein
electrophoresis and at least 50% decrease in
adenopathy/organomegaly on physical examination or on CT scan. No new
symptoms or signs of active disease.
Minor response (MR) At least 25% but less than 50% reduction of serum
monoclonal IgM by protein electrophoresis. No new symptoms or signs of active
disease.
A less-than-25% reduction and less-than-25% increase of serum monoclonal
IgM by electrophoresis without progression of
adenopathy/organomegaly, cytopenias, or clinically significant symptoms due to
disease and/or signs of WM.
Progressive
disease
(PD)
At least 25% increase in serum monoclonal IgM by protein electrophoresis
confirmed by a second measurement or progression of clinically
significant findings due to disease (ie, anemia, thrombocytopenia, leukopenia,
bulky adenopathy/organomegaly) or symptoms
(unexplained recurrent fever of at least 38.4°C, drenching night sweats,
References
Dimopoulous MA, Gertz MA, Kastritis E, et al. Update on Treatment
Recommendatinos from the fourth International Workshop on Waldenström’s
Macroglobulinaemia, J Clin Oncol. 27:120-126, 2008
Written by:
Dr Saad Abdalla, Dr Amin Rahemtulla, Dr Stephanie Kirschke, August 2009
Authorised by:
NWLCN Haematology TWG , March 2010,
Date for review by Haematology TWG: March 2011
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