|
Donna Weber1, Steven P. Treo
- n2, Christos Emmanouilides
- 3, Andrew R. Branagan -
2, John C. Byrd - 4,
Joan Blade - 5, and Eva Kimby
- 6.
The University of Texas, MD Anderson
Cancer Center, Houston, TX, USA
- 1, Dana Farber Cancer Institute, Harvard Medical
School, Boston, MA, USA - 2,
UCLA Medical Center, Los Angeles, CA, USA
- 3, Arthur James Comprehensive Cancer Center, Ohio
State University, USA - 4,
Institute of Hematology and Oncology, University of Barcelona,
Barcelona, SPAIN - 5, Karolinska
Institutet, Department of Hematology, Huddinge University
Hospital, Stockholm, SWEDEN - 6.
Waldenstromıs macroglobulinemia (WM)
is a malignant disorder of lymphoplasmacytic cells that
produce a monoclonal immunoglobulin M (IgM). Since the original
description by Jan Waldenstrom of three patients with symptoms
of hyperviscosity due to circulating monoclonal IgM, the
definition of WM has been controversial. Standardized criteria
for diagnosis have now been proposed, including the presence
of any IgM monoclonal protein and marrow and/or nodal lymphoplasmacytic
cells. Although previous response criteria have generally
incorporated parameters for monoclonal protein reduction
and/or improvement of marrow/nodal involvement, specific
and uniform response criteria are needed to facilitate comparisons
of response, remission duration, progression-free, and overall
survival in clinical trials similar to those previously
established for other diseases such as CLL, lymphoma, and
myeloma. This is of particular importance as new agents
are developed and evaluated. This manuscript represents
consensus recommendations for uniform response criteria
for use in assessing responses to treatment for patients
with Waldenströmıs macroglobulinemia (WM), which were prepared
in conjunction with the 2nd International Workshop held
in Athens, Greece during September 2002.
Waldenstromıs macroglobulinemia is a
malignant disorder of lymphoplasmacytic cells that produce
a monoclonal immunoglobulin M (IgM). Since the original
description by Jan Waldenstrom of 3 patients with symptoms
of hyperviscosity due to circulating monoclonal IgM, the
definition of Waldenstromıs macroglobulinemia has been controversial.1,2,3,4
Standardized criteria for diagnosis have now been proposed,
including presence of any IgM monoclonal protein and marrow
and/or nodal lymphoplasmacytic cells, and are more comprehensively
discussed in the final recommendations of Consensus Panel
1 of the Second International Workshop on Waldenstromıs
Macroglobulinemia.5 Although previous response criteria
have generally incorporated parameters for monoclonal protein
reduction and/or improvement of marrow/nodal involvement,
specific and uniform response criteria are needed to facilitate
comparisons of response, remission duration, progression-free,
and overall survival in clinical trials similar to those
previously established for other diseases such as CLL, lymphoma,
and myeloma. 6,7,8 This is of particular importance as new
agents are developed and evaluated. During the Second International
Workshop on Waldenstromıs Macroglobulinemia (Athens, 2002)
this consensus panel proposed guidelines for standardized
response criteria that were subsequently discussed, modified
and then summarized in this report. Presented are recommendations
for specific tests to document response, parameters to be
followed and subsequently define response, and special considerations
specific to Waldenstromıs macroglobulinemia.
Do IgM levels truly correlate
with disease burden?
The panel
first addressed the issue of how IgM should best be measured
and monitored. The panel concurred that the use of nephelometry
to determine total serum IgM levels was unreliable, and
recommended that serial measurements of IgM monoclonal protein
as determined by serum electrophoresis should be used to
follow disease burden in a particular patient.
The panel
also concurred that among patients with WM, serum IgM monoclonal
protein levels could not be used as a determinant of disease
burden, and therefore cannot be used to compare disease
burdens between patients, but once disease burden has been
established for a particular patient serial measurements
of IgM monoclonal protein by serum electrophoresis are useful
in following disease burden for an individual patient with
WM.
The panel
also expressed that the presence of cold agglutinins or
cryoglobulins may affect determination of IgM levels. Therefore,
testing for cold agglutinins and cryoglobulins should considered
as part of the initial evaluation of patients with WM in
whom there is a clinical index of suspicion for their presence,
and if present, serum samples should be re-evaluated under
warm conditions for determination of serum IgM monoclonal
protein levels.
Should IgM levels per se be the
sole determinants of response in Waldenstromıs macroglobulinemia?
IgM monoclonal protein levels as
determined by serum electrophoresis may be used as a determinant
of disease response to therapy in WM. However, increased
stringency needs to be employed for the determination of
a complete remission response state as further described
below.
Is the use of lymph nodal or
splenic response necessary to determining response in WM?
Can lymph node or splenic shrinkage lag behind IgM and therefore
complicate response determination?
Decreases in lymph node and spleen
size may lag IgM responses in certain patients, and conversely
IgM decreases may lag in certain patients where lymph nodal
and splenic responses have been observed. IgM monoclonal
protein levels may also be slow coming with certain therapeutics,
particularly nucleoside analogues and biological therapies
and therefore clinicians and clinical investigators should
consider following patients until their best overall response
so as to not miss a delayed response.
Should recovery of hematological
function be considered in response determinations in WM?
The panel considered arguments for
the inclusion of hematological recovery as part of the response
determination in WM. The panel felt that since anemia, as
well as thrombocytopenia and leukopenia could be impacted
by many mechanisms related to WM, other non-WM related disorders,
as well as by therapy itself with the notable example of
prolonged cytopenias post nucleoside analogue therapy, that
hematological recovery ought not be mandated as part of
the response criteria for WM. Moreover, the panel considered
that since there is such great heterogeneity in the presentation
of WM, and that for many patients hematological function
is not substantially compromised that inclusion of recovery
of hematological function for many WM patients was not appropriate.
The panel, however, recommended that since IgM served a
good marker for tracking disease burden in a particular
patient with WM, that its use was reasonable as a major
determinant for disease response along with evidence of
improvement in at least one sign, symptom or laboratory
abnormality for which therapy was initiated for the determination
of the PR status (as noted below), and resolution of all
signs, symptoms or laboratory evidence associated with disease
and normal bone marrow histological examination for demonstration
of a CR (as is also noted below).
Definitions of complete and partial
responses.
The panel recommended the following
criteria for use in determining clinical responses in WM:
Morphologic evaluation should be confined
for determination of CR. Although phenotypic analysis by
flow cytometry or immunohistochemistry may prove useful
in defining diagnostic and response criteria in the future,
the panel felt there was insufficient evidence to currently
require the use of these tests for response determination.
Complete Response (CR)
Complete disappearance of serum and urine
monoclonal IgM by immunofixation, resolution of adenopathy/organomegaly,
and no signs or symptoms that are directly attributable
to Waldenstromıs macroglobulinemia (unexplained recurrent
fever > 38.4° drenching night sweats, > 10% body weight
loss, hyperviscosity, or symptomatic cryoglobulinemia. Absence
of malignant cells by bone marrow histologic evaluation
is required.Reconfirmation of the CR status is required
at least 6 weeks later.
Partial Response (PR)
A > 50% reduction of serum monoclonal
IgM concentration on protein electrophoresis. and > 50%
improvement in bulky adenopathy/organomegaly on CT scan.
No new signs, symptoms, or other evidence of disease.
Not Evaluable (NE)
Insufficient
data/time for a determination of response to treatment.
When should a patient be considered
as having progressive disease or relapsing from a complete
remission?
The panel recommended the following
criteria for use in determining identifying patients who
did not attain a response, or who demonstrate progressive
disease after a response:
Progressive Disease (PD)
A greater than 25% increase in serum
IgM monoclonal protein levels from the lowest attained response
value as determined by serum electrophoresis, confirmed
by at least one other investigation, or progression of clinically
significant disease related symptom(s).
Relapse from CR
Reappearance
of serum IgM monoclonal protein levels as determined by
immunofixation studies, confirmed by at least one other
investigation, or progression of clinically significant
signs or symptoms attributable to disease, or development
of any other clinically significant disease related symptom(s).
The panel
also recommended that evidence of PD or relapse from CR
should not necessarily indicate that at this juncture therapy
needs to be re-initiated, and that the criteria proposed
by Consensus Panel Two with regard to criteria for initiation
of therapy should apply in these circumstances.
Use of imaging modalities in
WM to determine response: CT scans, MRI, Pet Scans.
The panel affirmed the use of computer
tomography (CT) scans as part of the response determination
for CR and PR status as noted above, however felt that insufficient
evidence existed at this time to recommend the routine usage
of MRI or PET scans in the management of WM.
Discussion
Quantification of Monoclonal
IgM
In patients with Waldenstromıs macroglobulinemia,
accurate measurement of monoclonal IgM is paramount. Total
immunoglobulin quantification by nephelometry is frequently
unreliable, particularly at higher levels, because of distorted
elevation due to polymerization. This is in addition to
overestimation at low levels of paraprotein because of the
inclusion of normal IgM.9,10 Therefore, for response evaluation
serial measurements of monoclonal paraprotein should be
performed using precise densitometry measurements on standard
serum protein electrophoresis. However, when the monoclonal
protein is either <0.5 g/dl or not quantifiable, determination
of IgM levels by nephelometry is acceptable. Because serum
immunofixation is more sensitive than serum protein electrophoresis,
complete remission (CR) should be confirmed by immunofixation
after the paraprotein is no longer detectable by routine
electrophoresis.
Although initial measurement of the monoclonal
IgM establishes a baseline for comparison of subsequent
serial measurements of paraprotein and response determination
in an individual patient, a particular level of monoclonal
IgM does not consistently relate to disease burden, and
therefore, monoclonal IgM cannot be used to determine tumor
mass between patients.
Since the presence of a cryoglobulins
can effect the quantification of monoclonal IgM, testing
for these at baseline should be considered, particularly
if the clinical index of suspicion for their presence is
high. If cryoglobulins are present, subsequent samples for
quantification of monoclonal IgM should always be collected
and transported at 37° C to insure accurate and consistent
determination of the paraprotein level.9
Quantification of Bence Jones
Protein
Bence Jones protein excretion in a sample
collected over 24 hours should be quantified by protein
electrophoresis. Although small quantities of Bence Jones
protein (BJP) are noted in approximately 50% of patients
with Waldenstromıs macroglobulinemia, BJP rarely, if ever,
impacts the clinical course of disease.11 Therefore, no
specific recommendations are necessary for reduction of
BJP in defining partial remission (PR). Complete remission,
however, reflects complete disappearance of disease and
should be confirmed by negative studies on urine immunofixation
if an abnormality had been present at diagnosis.
Documentation of Bone Marrow
involvement
Because of the macrofocal nature of bone
marrow infiltration in Waldenstromıs macroglobulinemia,
the panel recommended that bone marrow aspirate and biopsy
not be required for confirmation of PR, but absence of malignant
cells by morphologic evaluation should be confirmed for
determination of CR. Although phenotypic analysis by flow
cytometry or immunohistochemistry may prove useful in defining
diagnostic and response criteria in the future, the panel
felt there was insufficient evidence to currently require
the use of these tests for response determination.
Documentation of Lymphadenopathy/Organomegaly
Computed tomography (CT) scans of the
chest, abdomen and pelvis should be performed at baseline
to establish the presence of lymphadenopathy and/or organomegaly.
Improvement of significant bulky adenopathy/organomegaly
should be confirmed by CT scan if treatment was initiated
solely on this basis (bulky adenopathy/organomegaly). Resolution
of all adenopathy/organomegaly, and no new sites of disease,
by CT scan is necessary to confirm CR, and evaluation should
not be limited to sites of previous disease. In the rare
patient with bulky disease, as in other forms of lymphoma,
there may be difficulty interpreting response because of
residual masses after chemotherapy. For these rare patients
the panel recommended following the complete response unconfirmed
(Cru) criteria previously described by Cheson et al.7 There
is currently insufficient evidence to recommend routine
use of magnetic resonance imaging (MRI) or positron emission
tomography (PET).
Hematologic Response
Determination of remission based on hematologic
criteria is difficult since anemia and other cytopenias
may be due to etiologies other than Waldenstromıs macroglobulinemia.
Therapy with nucleoside analogues may also produce prolonged
cytopenias even in patients considered to be in remission
by other criteria. Because of these special considerations
the panel noted that the major determinant of partial response
should be reduction of monoclonal IgM and that no specific
criteria for hematologic response were recommended.
Response Criteria/Special Considerations
This consensus panel recommends the following
criteria as definitions of response/remission. Should future
testing of additional studies (ie MRI, PET scan, free light
chain assays, B2 microglobulin, etc) demonstrate confirmed
predictive value, these criteria may be revised. Clinical
response should not be assessed prematurely since reduction
of monoclonal IgM and improvement of associated disease
features may be slow (monthsyear), particularly after treatment
with nucleoside analogue or biologic therapies. Reductions
in adenopathy/organomegaly and hematologic recovery may
follow monoclonal protein response, or vice versa; therefore,
determination of best response should be assessed at disease
nadir to avoid missing a delayed response. To insure stability
of remission, response should be confirmed with a second
electrophoresis no earlier than 6 weeks after the initial
determination of response, and CR should be reconfirmed
by immunofixation no earlier than 6 weeks after the initial
negative immunofixation. The panel recommended that for
patients to be considered evaluable for lack of response
to treatment, they must have been followed for at least
3 months after treatment initiation. Specific definitions
for response are set forth below.
Relapse and Disease Progression/Special
Considerations
Although strict criteria are necessary
to define relapse/PD for comparisons of data in clinical
trials, progressive disease defined only by a small increment
in paraprotein, does not necessarily indicate a need for
retreatment in the absence of clinically significant signs
and symptoms attributable to Waldenstromıs macroglobulinemia.
Recommendations proposed by the Consensus Panel for Prognostic
Markers and Criteria to Initiate Therapy should be consulted
for specific treatment criteria.12
Relapse from CR
Reappearance of monoclonal serum IgM
by immunofixation confirmed by a second measurement and/or
progression of clinically significant signs (anemia, thrombocytopenia,
leukopenia, bulky adenopathy/organomegaly) or symptoms (unexplained
recurrent fever > 38.4° C, drenching night sweats, > 10%
body weight loss, or hyperviscosity, nephropathy, symptomatic
cryoglobulinemia or amyloidosis) directly attributable to
Waldenstromıs macroglobulinemia.
Relapse from PR
A > 25% increase in serum monoclonal
IgM by protein electrophoresis confirmed by a second measurement
or progression of clinically significant signs (anemia,
thrombocytopenia, leukopenia, bulky adenopathy/organomegaly)
or symptoms (unexplained recurrent fever > 38.4° C, drenching
night sweats, > 10% body weight loss, or hyperviscosity,
neuropathy, nephropathy, symptomatic cryoglobulinemia or
amyloidosis) directly attributable to Waldenstromıs macroglobulinemia.
For monoclonal protein nadirs < 2g/dl an absolute increase
of 0.5 g/dl is required to determine disease progression.
At relapse, reevaluation by CT scan,
particularly in patients with a high LDH, should be performed.
If any large masses are detected these should be biopsied
to confirm that transformation to an intermediate or high
grade lymphoma has not occurred.
Future Considerations
These criteria serve as initial guidelines
for determination of response in Waldenstromıs macroglobulinemia.
These criteria should be evaluated in large clinical trials
using cause-specific survival as the endpoint. Modification
of these guidelines may be appropriate as treatment improves
and if prospective analyses of other modalities to assess
disease, such as MRI, PET scans, B2 microglobulin, and free
light chain assays, indicate that one or more of these supplement
current criteria or more accurately determine response and
impact survival. In addition to promote timely evaluation
of novel agents for the treatment of Waldenstromıs macroglobulinemia,
investigators are also encouraged to report endpoints such
as time to treatment, since progression-free survival may
not define the point at which clinically significant relapse
has occurred.
References
1. Waldenstrom J: Incipient myelomatosis
or essential hyperglobulinemia with fibrinogenopenia
a new syndrome? Acta Med Scand 117:217-247, 1944.
2. Dimopoulos MA, OıBrien S,
Kantarjian H, et al: Treatment of Waldenstromıs macroglobulinemia
with nucleoside analogues. Leukemia Lymphoma 11:105-108,
1993.
3. Weber D, Dimopoulos MA, Rankin
K, et al: A decade of experience: Primary treatment of
Waldenstromıs macroglobulinemia (WM) with 2-chlorodeoxyadenosine
(2-CdA) alone or in combination. Blood 98(11), 2660, 2001
(abstract).
4. Hellmann A, Lewandowski K,
Zaucha JM, et al: Effect of a 2-hour infusion of 2-chlorodeoxyadenosine
in the treatment of refractory or previously untreated
Waldenstromıs macroglobulinemia. Eur J Haematol 63:35-41,
1999.
5. Dimopoulos MA, Owen R, et
al: Consensus Panel 1 of the Second International Workshop
on Waldenstromıs macroglobulinemia: Clinicopathological
definition of Waldenstromıs macroglobulinemia Semin Oncol
(in press).
6. Blade J: Criteria for evaluating
disease response and progression in patients with multiple
myeloma treated by high-dose therapy and haemopoietic
stem cell transplantation. Br J Haematol 102:1115-1123,
1998.
7. Cheson BD, Horning SJ, Coiffier
B, et al: Report of an international workshop to standardize
response criteria for non-Hodgkinıs lymphoma. J Clin Oncol
17:1244-1253, 1999.
8. Cheson BD, Bennet JM, Grever
M, et al: National Cancer Institute-sponsored Working
Group for chronic lymphocytic leukemia: Revised guidelines
for diagnosis and treatment. Blood; 87:4990-97, 1996.
9. Alexanian R, Weber D, Liu
F: Differential diagnosis of monoclonal gammopathies.
Arch Pathol Lab Med 123:108-113, 1999.
10. Keren DF, Alexanian R, Goeken
JA, et al: Guidelines for clinical and laboratory evaluation
of patients with monoclonal gammopathies. Arch Pathol
Lab Med 123:06-107, 1999.
11. Dimopoulos MA, Alexanian
RA: Waldenstromıs macroglobulinemia. Blood 83:1452-1459.
12. Kyle R, Leblond V, Barlogie
B, et al: Consensus Panel 2 of the Second International
Workshop on Waldenstromıs macroglobulinemia: Prognostic
markers and criteria to initiate therapy in Waldenstromıs
macroglobulinemia Semin Oncol (in press).
|
