Opening Session
- Defining Waldenstrom's Macroglobulinemia, Steven Treon, MD
- Macroglobulinemia, Marvin Stone, MD

Defining Waldenstrom's Macroglobulinemia
Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute, Boston, MA

Almost sixty years after its identification, physicians are still wrestling with the nature of Waldenstrom's macroglobulinemia, and seeking the best treatments for it.

In 1943, Jan Waldenstrom, a Swedish physician, came across a new syndrome, which he thought at the time might be an early phase of multiple myeloma. Two patients displayed an infiltration of the bone marrow by lymphocytes, and in their blood a large amount of a heavy protein (IgM), which he described as being "monoclonal," all molecules being identical. Only later did he realize that what he had found was a distinct disease.

His confusion is understandable. As we now know, many blood disorders can raise the IgM level. In addition to multiple myeloma, the catalog includes CLL, NHL, amyloidosis and MGUS. In addition, infections like hepatitis, AIDS, and the various rheumatological diseases can also raise IgM levels.

So an elevated IgM level in and of itself is not proof that a patient has WM. Though recently categorized as a lymphoplasmacytic lymphoma by the World Health Organization, we not yet put a finger on a characteristic chromosomal aberration, or an identifying marker on the cellular surface. The task of definitively describing the disease is not yet complete. One of the tasks set for the Second International Workshop on Waldenstrom's Macroglobulinemia, to take place in Athens in the year 2002, is to define clearly diagnostic criteria for the malady.

A great deal of work is currently being done toward those definitions. Of particular interest is the employment of new technologies, for example the lymphochip, by which we can hope to see what genes are turned on in the Waldenstrom's cell that are dormant in normal cells. We also need to look for factors identifying the likely aggressiveness of the disease in a given patient, such as elevation of beta-2 microglobulin, decreased blood cell counts, age and gender. One such system is being looked at by Pierre Morel and others in France, tying life expectancy to the number of blood cell lines (reds, whites, and platelets) showing suppression, forecasting survival rates of ten, five and three years if one, two, or all three lineages were suppressed.

If we can create a uniform prognostic system, that will help us in making therapeutic choices for individual patients. Most notably, in such an indolent yet so far incurable malady, there is the question of when therapy should be started, if at all. Robert Kyle, for example, followed patients over the course of forty years. What he found was that most patients with high IgM levels would not become malignant at all. They have a condition known as MGUS (monoclonal gammopathy of unknown significance). We should, therefore, wait for the tumor to develop before assuming the patient has WM and needs treatment.

Another question to which we need to find an answer is how cancer cells escape detection and destruction by the immune system, which routinely kills off other defective cells. We now have some clues, including soluble TRAIL proteins which kill those cells of the immune system that would otherwise find and destroy tumor cells. And we have identified proteins on the cancer cell walls, such as MUC-1 and CD59, that act as physical barriers, almost like barbed wire, barriers keeping attacking cells from getting close enough to kill.

All of these questions will be looked at closely at the Athens meeting. But certain conclusions can already be reached:
1) The severity of the disease cannot be determined simply on the basis of the quantity of IgM protein in the blood. It can, however, be predicted either on the basis of the level of beta-2 microglobulin or from the suppression of normal blood cell counts.
2) Initiation of therapy should be determined less on the basis of the figures than on symptoms - hyperviscosity, low blood counts, peripheral neuropathy, etc.
Once the need for therapy is established, what therapy should be adopted? A plethora of treatments is available:
1) Plasmapheresis - a stopgap measure but giving immediate relief to symptoms of hyperviscosity.
2) Alkylating agents used singly - the traditional chemotherapeutic approach using chlorambucil, melphalan or similar compounds.
3) Nucleoside analogs - 2CdA, fludarabine, pentostatin
4) Combination chemotherapy - COP, CVP, CHOP and the like.
5) Non-chemos such as rituximab or thalidomide.
6) Blood or marrow transplants, either from one's own stored stem cells or those of a matched donor.
7) Newer drugs as they come on line (Campath, PS341, Zevalin, Antisense, etc). Many of these newer compounds are available through clinical trials (mostly in Phase II). This is important, because to prove the way we ought to go we need randomized studies to compare treatments - and this means we need volunteer patients to take part in these trials.
Finally, we need a standardized way of telling whether and how well the disease is responding to whatever treatment we may be using. This, too, is one of the goals we have set for ourselves to accomplish at the 2002 summit in Athens.

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Macroglobulinemia
Marvin Stone, MD, Baylor-Sammons Cancer Center, Dallas, TX

We have known Waldenstrom's macroglobulinemia as a disease separate from multiple myeloma for five decades now. The basic feature is a high concentration of macroglobulin of the IgM type in the blood. In some patients these macroglobulins act as immunizing proteins just as they would in healthy individuals; in other cases they do not.

The symptoms of the disease are usually ascribable simply to the great quantity, either of the heavy protein in the bloodstream, or of the associated lymphocytes in the bone marrow where they squeeze out other cells. These lymphocytes are the reason for the current classification of WM as a "lymphoplasmacytic" lymphoma. While there may be some associated loss of bone mass, bone lesions of the type seen in multiple myeloma are rare. But, like MM, it is a disease in which anemia is common; and it can lead to amyloidosis, the depositing of protein in the muscle fiber.

Diagnosis of Waldenstrom's macroglobulinemia is dependent upon the presence of one or more of several factors:

1) Examination of the protein in the blood serum shows a "monoclonal gammopathy," a high concentration of identical protein molecules.
2) A blood smear is often abnormal; the heavy protein coats the red cells and they therefore tend to clump together.
3) The "molasses-like" nature of the serum causes red cells in a tube of blood to settle to the bottom much more slowly than usual.
4) Many B-cell lymphocytes, with large cytoplasm, are found in the marrow. A number of different varieties are found, but in a given patient one type predominates.
5) The hyperviscosity (molasses-likeness) of the blood forces expansion of the capillaries. In the eyes, one can see capillaries looking like little sausages; if they burst, retinal damage may result. Ninety percent of hyperviscosity cases turn out to be WM.
6) Unexplained bleeding may occur in the skin and mucous membranes, because platelets, covered with IgM protein, can't properly stick together to stop leaks.
7) There are a number of associated neurological disorders, the most common of which is peripheral neuropathy. The nerves, usually in the hands or feet, cease to function properly, and the result is sensory or motor problems in the affected areas.
8) A few patients show cryoglobulinemia, in which abnormal proteins precipitate from the blood when cooled below body temperature; or cold agglutinins may attach to and destroy red blood cells, producing anemia.

For most of these symptoms there is a quick and dirty cure - plasmapheresis. By physically removing the heavy protein from the blood serum, you remove the direct cause of most of the difficulties. But it is a temporary fix. The B-cells in the bone marrow keep producing IgM, and it soon builds up again in the blood serum.

To understand why the viscosity problems occur in the first place, remember that IgM is a BIG molecule. In terms of elementary chemistry, one mole would weigh a ton. It has a molecular weight around nine hundred thousand!

What other phenomena, besides an extremely heavy protein gooking up the blood, are typical of Waldenstrom's?

1) The bone marrow is always involved. That is where the malignant B-cells proliferate.
2) Lymph nodes, spleen and liver, alone or in combination, may sometimes be affected, but not always. About one third of patients have enlarged lymph nodes; two thirds do not.
3) At the cellular level, the CD20 surface marker is almost always present.

Peripheral neuropathy, incidentally, may sometimes be caused by the simple fact of the presence of so much very heavy protein. Or it may sometimes be due to the IgM protein acting as if the nerve tissue were an invading irritant and attacking it, particularly stripping away the nerve's protective myelin sheath.

So there are many things that may lead to a diagnosis of Waldenstrom's macroglobulinemia. But there are no generally accepted criteria or levels of staging. What you generally see is a division of patients with high IgM into three subsets:

1) MGUS (monoclonal gammopathy of unknown significance) - a stable though excessive production of IgM that may go on for years.
2) Lymphomas other than Waldenstrom's that produce macroglobulins in greater than the usual quantity.
3) "Genuine" Waldenstrom's macroglobulinemia.

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