Fall 2007 - International Waldenstrom's Macroglobulinemia ...

Research Clinical Highlights, cont from page 6
leukemia (AML), or transformation of WM to diffuse
large B-cell lymphoma (DLBCL) with the use of
nucleoside analogs, particularly fludarabine, was
felt to need more data and review before a consensus
statement could be made.
• It is too early to recommend rituximab maintenance
as long-term data are not yet available.
• Age is an important factor for deciding which initial
monotherapy to use (age 65 is the unofficial cut-off
point); however, the measurable Performance Status
of the patient is very important (a “young” 70 year
old as opposed to a very sick 45 year old).
• Special attention and caution are needed when
using lenalidomide (Revlimid) in WM because of a
possible rapid onset anemia (this is not seen in MM
or CLL).
• Autologous bone marrow transplants are
increasingly viewed as valuable therapeutic options
for the appropriate patient as the data on survival and
duration of remissions are superior to many other
conventional treatments.
• Allogenic transplants should only be considered
when absolutely necessary and in the context of a
clinical trial. See the above comments on RIC or
mini-allo transplants, which may be appropriate in
exceptional cases.
ORAL AND POSTER PRESENTATIONS
Genetics, Pathophysiology and Staging System
Many new and exciting discoveries are being made in the
biology of WM. To date, however, problems still arise in the
accurate differentiation between WM and other similar non-
Hodgkins B-cell immunoglobulin (Ig) secreting lymphomas.
Of particular interest is the family tree of the WM cell and
determining the cell of origin along the B cell developmental
path that gives rise to the WM tumor cell. Most current
research has centered on the WM cell’s inability to “switch”
from the initial production of IgM to the production IgG or
IgA (see the IWMF publication “Introduction to Immunology
in WM”). From the study of this “class switch” phenomenon
(from IgM to IgG and IgA), which is arrested at the IgM
level in WM (neoplastic arrest), and from the study of the
immunoglobulin gene rearrangements, mutations, and class
switch recombination, scientists are gaining insight into
the dissimilarities between WM and IgM-MGUS. (MGUS
refers to “monoclonal gammopathy of undetermined
significance,” which is specified as IgM-MGUS in cases
where the monoclonal protein is IgM.) This could suggest
a distinct differentiation process between WM and IgM-
MGUS. Furthermore, these studies will enable scientists to
identify the differences and similarities between WM and
other B-cell lymphoproliferative disorders, and this, in turn,
can help to explain how the WM tumor cell is produced in
the B-cell differentiation process.
Dr. Linda Pilarski, a research scientist at the University
of Alberta Cross Cancer Institute and a recipient of a large
IWMF research grant, has focused her research on hyaluronan
synthase 1 (HAS1). This large sugar molecule is important
in cell motility, signaling, and mitosis (cell division). Dr.
Pilarski’s laboratory has identified three different gene variants
of HAS1, two of which are the result of partial retention of
a particular segment of DNA in the gene (an intron) that
is found only in patients with WM or multiple myeloma.
“Intronic splicing” is seen only in cancer cells and is not
found in the cells of healthy individuals. The identification
of these gene variants holds promise of the development of a
DNA lab test permitting not only individual risk assessment
strategies for early detection and monitoring of malignancy
before, during and after therapy, but also assessment of
response and prediction of relapse. Furthermore, the pattern
of tumor-specific DNA mutations may provide a common
marker, or ID tag, for all such patients. It may also be possible
to use DNA lab testing to monitor IgM-MGUS for the early
stages of emerging malignancy, response to treatment, and
identification of the monoclonal gammopathies that have the
greatest risk of transformation to WM.
Dr. Rafael Fonseca, a clinical researcher from the Mayo
Clinic in Scottsdale, Arizona, and an IWMF research
grant recipient, has also focused on the genetics of WM.
His prolific gene expression profile studies have recently
suggested that WM shares more similarities with chronic
lymphocytic leukemia (CLL) than multiple myeloma (MM).
Dr. Pilarski, however, contests this observation because her
lab research suggests that WM is closer to MM, not CLL. Dr.
Fonseca argues that, while clinically similar, the cytogenetics
and genomics underlying MM and WM are quite different.
The genetics of WM appears to be much simpler than those
of MM, with fewer abnormalities (the 6q deletion is the
most frequent abnormality in WM, observed in 16% of
WM patients). Newer laboratory tools, such as array-based
comparative genomic hybridization and gene expression
profile, enable researchers to realize high-resolution whole
genome screenings for abnormalities and to gain insight into
the consequences of genomic alterations noted in WM. As is
the hope of many WM patients, future therapeutic decisions
may be based solely on practical clinical tools such as
genomic studies.
Dr. E. Morra of Italy evaluated the existing diagnostic
criteria used to separate IgM-MGUS from SWM (smoldering
or asymptomatic WM). Until recently, a reliable distinction
of asymptomatic populations with different risks of
transformation into active disease was not available. The 2 nd
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