Defining Waldenstrom Macroglobulinemia

Insights From: Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute


Steven P. Treon, MD, PhD: Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma. This is a mature B-cell lymphoma that also has the ability to differentiate into plasma cells. So you see a combination of mature B cells, lymphoplasmacytic cells, and plasma cells in the bone marrow of a patient with this disease. These are all clonally related cells. They all carry the same mutation. In almost all patients, we see the MYD88 mutation. So they see it in all the different cell types that make up the disease.

Among the lymphoplasmacytic lymphomas, it’s the most common. Almost 95% of them actually secrete immunoglobulin M (IgM). So even though the word Waldenström is almost synonymous with IgM lymphoplasmacytic lymphoma, it’s important to keep in mind that there are other types of lymphoplasmacytic lymphomas: IgG [immunoglobulin G], IgA [immunoglobulin A], and nonsecreting as well.

The symptoms that patients present with in Waldenström can vary a lot, and that’s why it’s important to keep the symptoms in mind. For the typical patient, anemia is very important to keep in mind. There are many mechanisms under which anemia can be produced. It can be because the disease has spread in the bone marrow and is inhibiting the red blood cell–producing cells from having space to be able to grow out of red blood cells. It can be because of hemolytic anemia, in which the antibody associated with the Waldenström, the IgM, can bind to red blood cells and cause their destruction.

There’s also this very interesting protein called hepcidin that’s produced by the tumor cells in response to the interleukin-6, which is elevated in the bone marrow of patients with Waldenström. Hepcidin actually causes the loss of the ability to absorb iron by the gut. It also triggers whatever iron there is in the body to be sequestered in macrophages and monocytes. And so, even if you stain a bone marrow to look for iron reserves, you’ll first think, “Well, there’s iron there.” But when you look very closely, that iron is in the monocytes and macrophages. This can produce anemia. We see this a lot in patients with Waldenström. Sometimes we treat them with parenteral iron to overcome that gut blockade. This can actually help the patients recover their hemoglobin very quickly. However, it is an insidious mechanism by which patients can become anemic with Waldenström. Of course, there are other cytopenias that can be produced because of the expansion of the tumor cells in the bone marrow.

It’s also important to keep in mind that in almost half of all patients, it’s not because of tumor bulk in the bone marrow that they’re symptomatic. It’s because of the IgM. IgM is a big, bulky molecule. It weighs almost 1 million Da. Almost 80%, 90% of the IgM that you and I make stays in the bloodstream. As a result, it can have an undue effect on the viscosity of the blood. If you have too high of an IgM level, your serum viscosity can be high, and you can have all kinds of symptoms. Usually retinal bleeding is what we see. Nose bleeds can also occur. So when you see it, this represents an oncological emergency.

The IgM can also act as an autoantibody. It can attack the peripheral nerves. They’re usually anti-demyelinating or demyelinating antibodies, stripping away the insulation around peripheral nerves. Almost a quarter of the patients who we now see come in because they have peripheral neuropathy diagnosed by the neurologist. Those are the people whom we are diagnosing Waldenström in because they routinely get serum protein electrophoresis as part of the workup for peripheral neuropathy. We also tend to see a cold agglutinin anemia. We can see cryoglobulinemia because of the IgM antibody. These are examples of presenting reasons why these patients get referred to us.

Adenopathy, at least at presentation, is very rare. We see it in only about 15% of all cases. At the time of relapse, it can be much more. It can occur in up to half of all patients. So it’s not as frequent a reason why we would initiate therapy, but it’s important to keep in mind.

The last thing to keep in mind is that sometimes patients can present with Waldenström in the central nervous system (CNS), or they can relapse with Waldenström in the CNS. It used to be a very rare occurrence that we saw CNS involvement by Waldenström, which is referred to as Bing-Neel syndrome. Now we see 3 to 4 or maybe even 5 cases a month in our clinic. It’s becoming far more common, maybe because we’re getting better at diagnosing it, but also because it’s a sanctuary cycle and we see a lot of relapses occurring.

Transcript Edited for Clarity 
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