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Robert A. Kyle - 1, Steven P. Treon
- 2, Raymond Alexanian - 3, Bart Barlogie - 4, Magnus Bjorkholm
- 5, Madhav Dhodapkar - 6, T. Andrew Lister - 7, Giampaolo
Merlini - 8, Pierre Morel - 9, Marvin Stone - 10, Andrew
R. Branagan - 2, Veronique Leblond - 11
Mayo Clinic, Rochester, MN, USA1, Dana
Farber Cancer Institute and Harvard Medical School, Boston
MA, USA - 2, The University
of Texas M.D. Anderson Cancer Center, Houston, TX, USA3,
Myeloma Institute for Research and Therapy, Little Rock,
AR, USA - 4, Department of
Medicine, Karolinska Hospital and Institutet, Stockholm,
SWEDEN - 5, Laboratory of
Tumor Immunology and Immunotherapy, The Rockefeller University,
New York, NY 10021, USA - 6,
Department of Oncology, St Bartholomew¹s Hospital, London,
UK - 7, Biotechnology Research
Laboratories, University Hospital IRCCS Policlinico San
Matteo, Department of Biochemistry, University of Pavia,
Pavia, ITALY8, Service d¹Hematologie Clinique, Centre Hospitalier
Schaffner, Lens, FRANCE9, Baylor Charles A. Sammons Cancer
Center, Dallas, TX, USA10, and Departement d¹Hematologie,
Hopital Pitie-Salpetriere, AP-HP, Paris, FRANCE1
- 1
This manuscript represents consensus
recommendations on prognostic markers and criteria to initiate
therapy in patients with Waldenstrom¹s macroglobulinemia
(WM), which were prepared in conjunction with the 2nd International
Workshop held in Athens, Greece during September 2002. The
panel recommended that initiation of therapy should not
be based on the IgM level per sé since this may not correlate
with the clinical manifestations of WM. The consensus panel
agreed that initiation of therapy was appropriate for patients
with constitutional symptoms such as recurrent fever, night
sweats, fatigue due to anemia, or weight loss. The presence
of progressive, symptomatic lymphadenopathy or splenomegaly
provide additional reasons to begin therapy. The presence
of anemia with a hemoglobin value of £ 10 g/dL or a platelet
count <100x109 /Ldue to marrow infiltration also justifies
treatment. Certain complications such as hyperviscosity
syndrome, symptomatic sensorimotor peripheral neuropathy,
systemic amyloidosis, renal insufficiency, or symptomatic
cryoglobulinemia may also be indications for therapy. Recommendations
for follow-up of watch and wait patients are that patients
with monoclonal gammopathy of undetermined significance
(MGUS) should have serum protein electrophoresis repeated
each year. Patients with asymptomatic (smoldering) macroglobulinemia
should be followed every six months. Regarding prognostic
markers, hemoglobin and beta-2 microglobulin levels at diagnosis
are important prognostic markers in WM; they influence the
timing of treatment and survival. Age is a consistently
important prognostic factor for survival. However, the panel
felt that current data are inadequate to support the use
of any prognostic marker to select the timing and type of
therapy, and called for studies on the application of prognostic
markers in WM. .
Waldenström¹s macroglobulinemia is characterized
by the proliferation of B-lymphocytes that produce an IgM
monoclonal protein. This broad definition includes persons
with monoclonal gammopathy of undetermined significance
(MGUS) of the IgM type, lymphoma, primary amyloidosis (AL),
chronic lymphocytic leukemia (CLL), and Waldenström¹s macroglobulinemia
(WM). Previously WM had been defined as a malignant B-cell
proliferative disorder with an IgM monoclonal protein of
3 g/dL or more. However, many patients with bone marrow
or nodal infiltration by monoclonal lymphocytes or plasmacytoid
lymphocytes producing anemia, constitutional symptoms, hepatosplenomegaly,
and lymphadenopathy require treatment but do not have a
monoclonal protein > 3 g/dL. Furthermore, there is no difference
in survival or most clinical features based on the size
of monoclonal protein except for a greater likelihood of
hyperviscosity with higher IgM levels. Consequently, from
a treatment perspective, there is no rationale for separating
patients based on the level of monoclonal IgM.
Patients may present with a large monoclonal
protein (> 3 g/dL) and have a significant infiltration of
the bone marrow with lymphocytes and plasma cells but have
no constitutional symptoms, significant hepatosplenomegaly,
or lymphadenopathy. They also have little or no anemia.
Biologically these patients have an MGUS, but their serum
M-protein and bone marrow involvement is much greater than
one sees in MGUS. These patients are classified as smoldering
or asymptomatic macroglobulinemia. Patients with asymptomatic
monoclonal IgM < 3 g/dL, hemoglobin > 12 g/dL, and absence
of symptomatic lymphadenopathy or splenomegaly may be classified
as having IgM-MGUS. This condition is discovered by chance
and is the most common diagnosis among individuals with
a monoclonal IgM. Differentiation of IgM-MGUS from asymptomatic
WM may be difficult. Nevertheless, both are followed without
treatment. Some patients may have symptoms due to the biological
effects of the monoclonal IgM protein. Such patients may
have symptomatic peripheral neuropathy, cryoglobulinemia,
cold agglutinin disease, or AL amyloidosis. These patients
need treatment to control complications from the monoclonal
IgM produced by a small clone of lymphocytes.
Patients with asymptomatic or smoldering
macroglobulinemia should be recognized and not treated because
they may remain stable for many years. In this situation
the advice of Jan Waldenström, "Let well alone" must be
kept in mind (1). He emphasized the temptation to begin
chemotherapy in order to obtain "normal values" in the patient.
Waldenström also emphasized the need to listen to the patient
and to perform a careful physical examination and to avoid
treatment of a symptom. These patients should not be treated
simply on the basis of a laboratory abnormality such as
a large monoclonal serum protein or on the basis of a pathology
report indicating significant infiltration of the bone marrow
with lymphoid cells. Waldenström also emphasized the importance
of "quality of life." If the patient is able to state on
his tombstone the words of the great Swedish poet, Stiernhielm,
"Vixit, dum vixit, laetus" (He lived happily as long as
he lived) the physician has succeeded in improving the quality
of life of the patient.
The median survival of patients with
WM averages 5 years, but at least 20% of patients survive
for more than 10 years, and 10-20% die from unrelated causes
(2, 3, 4). Because WM is an uncommon disorder, relatively
few studies have defined prognostic factors in large patient
populations. Although several studies have analyzed prognostic
factors for survival in WM (3-13), only three multivariate
analyses have yielded prognostic scoring systems based on
large series (6,8,9)(Table 1). In the Italian study, the
criteria that discriminated two prognostically different
populations were age, weight loss, hemoglobin level and
cryoglobulinemia (6). A recent multivariate analysis of
the overall survival on 215 patients with a longer follow-up
found four prognostic markers: beta-2 microglobulin, hemoglobin,
albumin and age (7). In the French study a combination of
age, albumin, and blood cell counts provided a simple prognostic
model for survival (8). 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 below 4 g/dL
were significant adverse prognostic factors for survival
(9). A staging system using these variables identified four
distinct subsets of patients with estimated 5-year survival
rates of 87%, 64%, 53%, and 12%.
Many other prognostic factors have been
described in smaller series of patients, such as gender,
B symptoms, the IgM level, performance status, hyperviscosity,
the bone marrow infiltration pattern and cytogenetic abnormalities
(3-13), but patient numbers were small, follow-up was frequently
short, and multivariate analysis was often not performed.
Survival appears to be better in patients who respond to
therapy than in those with resistant disease. The response
can therefore be considered as a potential surrogate of
survival but not as a prognostic factor (5,14,15). In contrast,
it remains to be shown whether complete remission confers
a survival benefit.
The expert panel separated factors used
to determine the need for initiation of treatment from factors
predictive of survival.
1. Factors identifying patients likely
to require treatment in the short term
Hemoglobin and beta-2 microglobulin
levels at diagnosis are important factors for predicting
whether treatment will be required in the relative short
term. Additional studies though are needed to validate if
these, as well as other prognostic markers, can be used
to determine initiation and selection of therapy.
Discussion
In three studies (3,9,16) normal serum
beta-2 microglobulin level and a hemoglobin level of at
least 12 g/dL (9), 12.5 g/dL (3) or 11.5 g/dL (16) at diagnosis
identified a subset of patients who were less likely to
require therapy in a short term. Hemoglobin level < 12.5
g/dL was also shown to predict transformation into active
disease requiring treatment (17).
2. Factors predictive of the overall
survival:
Age is consistently an important
prognostic factor (Dimopoulos > 60 y (5), Dhodapkar > 70
y (9), Garcia-Sanz > 65 y (3), Merlini >60 y (7), Kyrtsonis
> 65 y (10), Gobbi > 70 y (6), Morel > 65 y (8). But this
factor is impacted by unrelated diseases and could disappear
as a factor in analyses using cause-specific survival (16).
Anemia, which reflects both marrow infiltration and the
serum level of monoclonal protein, was an adverse prognostic
factors: the hemoglobin level is a strong predictor of the
survival rate in all published series: Hb < 10.5 g/dL (2),
Hb < 9 g/dL (5), Hb< 10g/dL (6) and < 12 g/dL (8,9) Cytopenia
is also regularly identified as a significant survival predictor.
However, the precise levels of cytopenia with prognostic
significance remain to be determined. Some series have identified
the platelet count (< 150x109 /L (8) < 120x109/L (6) and
the white blood cell count (< 4x109 /L (8) as independent
prognostic factors. The number of types of cytopenia in
a given patient has been proposed as a strong prognostic
factor (8,10). Serum albumin level was correlated with survival
in two main WM populations by multivariate analysis (7,
8) but not identified in other studies (3, 10). High beta-2
microglobulin values were linked to poor survival in all
the studies in which they were analyzed (3,7,9). A precise
cutoff value for this parameter has to be determined in
future studies.
Discussion
Hemoglobin and beta-2 microglobulin levels
at diagnosis are important prognostic markers in WM: they
appear to influence the timing of treatment and survival.
The precise levels of hemoglobin and beta 2-microglobulin
with prognostic significance remain to be determined, however.
Age is consistently an important prognostic factor for survival.
Serum albumin level is correlated with survival in two main
WM populations. Other parameters such as other cytopenias,
bone marrow pathological findings, hyperviscosity, performance
status, the Morel, Dhodapkar and Gobbi scores and biological
data such as the IgM level, and cytogenetics need to be
validated in prospective studies. Additional studies are
needed to determine whether these and other prognostic markers
can be used to decide on the initiation and selection of
therapy.
Should prognostic markers be
used in the decision making process for recommending initiation
and type of therapy, including participation in a clinical
trial?
The panel felt that insufficient
data exist at the present time to affirm the use of any
prognostic marker in the initiation and selection of therapy,
and identified studies into the application of prognostic
markers in WM as an important area of need.
Clinical and Laboratory considerations
for initiation of therapy in WM.
The panel
recommended that a thorough history, physical examination
including funduscopic examination to exclude retinal vein
engorgement with hemorrhaging and exudates, and papilledema
and determination of a serum viscosity level determinations
(if available) should be undertaken at initial examination
and on follow-up examinations as needed for evaluation of
hyperviscosity.
The panel
also considered that the use of densitometry should be adopted
to determine IgM levels for serial evaluations since nephelometry
remains unreliable and shows large intra-laboratory as well
as inter-laboratory variation.
The panel
considered that initiation of therapy should not be based
on consideration of IgM levels per se, since these may not
correlate with clinical manifestations of WM. However, initiation
of therapy is reasonable for those patients who demonstrate
rising IgM levels with progressive signs or symptoms of
disease.
The panel
considered that initiation of therapy was appropriate for
patients who demonstrated a hemoglobin of <10 g/dL, and/or
platelet count of <100x109 /L which were attributable to
disease, bulky adenopathy or organomegaly, or any other
disease related complaints which were serious enough to
warrant therapy including recurrent fever, night sweats,
weight loss, fatigue, or symptomatic manifestations associated
with WM including hyperviscosity, symptomatic neuropathies,
nephropathy, amyloidosis, symptomatic cryoglobulinemia,
or evidence of disease transformation. In the absence of
the above, close observation of patients was reasonable.
The panel
considered that patients who demonstrated signs or symptoms
suggestive of symptomatic hyperviscosity should be considered
for immediate plasmapheresis, and initiation of chemotherapy
as soon as possible.
Discussion
Patients with constitutional symptoms
such as recurrent fever, night sweats, fatigue due to anemia,
or weight loss are indications for therapy. The presence
of progressive, symptomatic lymphadenopathy or splenomegaly
provide additional reasons to begin therapy. The presence
of anemia with a hemoglobin value of £ 10 g/dL or a platelet
count <100x109 /Ldue to marrow infiltration also justifies
treatment. Certain complications such as hyperviscosity
syndrome, symptomatic sensorimotor peripheral neuropathy,
systemic amyloidosis, renal insufficiency (rare), or symptomatic
cryoglobulinemia may also be indications for therapy. Initiation
of therapy should not be based on the IgM level per sé since
this may not correlate with the clinical manifestations
of WM. The use of densitometry should be adopted to define
IgM levels for serial evaluation because nephelometry may
produce erroneous elevations and is associated with considerable
inter- and intralaboratory variation. Initiation of therapy
is reasonable for those patients who demonstrate rising
IgM levels associated with progressive signs or symptoms
of disease. Patients who demonstrate signs or symptoms suggestive
of symptomatic hyperviscosity should be considered for immediate
plasmapheresis and initiation of chemotherapy.
An IgM level > 3 g/dL places patients
at higher risk for hyperviscosity and requires a thorough
history for evidence of oronasal bleeding, blurred vision,
headache, dizziness, vertigo, ataxia, encephalopathy, or
altered consciousness. Funduscopic examination is necessary
to detect signs of hyperviscosity such as venous dilatation,
"sausage formation" hemorrhages, and exudates. Measurement
of serum viscosity should be performed if available. The
correlation between serum viscosity levels and symptoms
is often poor from patient to patient. However, the serum
viscosity level correlates well with clinical signs and
symptoms in the same patient. Most patients with a serum
viscosity < 4 cp will not have symptoms of hyperviscosity
(normal = 1.8 cp).
Recommendations for follow-up of watch
and wait patients.
For asymptomatic (smoldering) WM
patients, close interval follow-up is recommended (every
3-6 months). For patients with the diagnosis of IgM monoclonal
gammopathy of undetermined significance (MGUS), serum IgM
levels should be rechecked at 3 months, and if stable, annual
follow-up thereafter would be considered reasonable. The
patient should be advised to return to the physician in
the event of any symptoms or untoward problems.
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Table 1: Multivariate analyses of survival
in WM with prognostic scoring system
| Study |
Prognostic factors |
Number of groups |
Survival |
| Gobbi et al (5) |
Hb < 9 g/dL
Age > 70 y
Weight loss
Cryoglobulinemia |
0-1 prognostic factor
2-4 prognostic factors
|
Median survival: 48 months
Median survival: 80 months
|
| Morel et al (7) |
Age * 65y
Albumin < 4 g/dL
Total number of cytopenia:
· Hb < 12 g/dL
· Platelets < 150x109/L
· White blood cell count < 4x109/L
|
0-1 prognostic factor
2 prognostic factors
3-4 prognostic factors
|
5-y survival rate: 87%
5-y survival rate: 62%
5-y survival rate: 25%
|
| Dhodakpar et al (8) |
*2-microglobulin * 3mg/L
Hb < 12 g/dL
IgM < 4 g/dL
|
*2-M < 3 mg/L + Hb
* 12 g/dL *2-M < 3 mg/L + Hb < 12 g/dL
*2-M* 3 mg/L+ IgM * 4 g/dL
*2-M * 3 mg/L + IgM < 4 g/dL
|
5-y survival rate: 87%
5-y survival rate: 63%
5-y survival rate: 53%
5-y survival: 21%
|
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