Managing common and uncommon complications of WM

Introduction

Waldenstrom’s macroglobulinemia (WM) is a rare type of B-cell lymphoma accounting for 1–2% of all hematologic malignancies, with a high prevalence among older adults. It presents as an accumulation of lymphoplasmacytic cells and the overproduction of monoclonal IgM proteins, both of which affect the clinical sequelae.¹ Complications of WM derive from the direct presence of infiltrated lymphoplasmacytic cells in the bone marrow and other organs, as well as the physical and immunological properties of the monoclonal IgM protein.²

In this review, we discuss the pathogenesis of common and uncommon clinical complications of WM relating to direct tumor infiltration, physical properties of the circulating monoclonal IgM, and interactions of IgM with proteins and tissues. We will also discuss the relevant management strategies, as presented by Ansell at the 2022 IWMF Educational Forum.²

Complications derived from lymphoplasmacytic infiltrate

Morphologically, the lymphoplasmacytic filtrate has a predominant intertrabecular pattern. Immunophenotypic features include cell surface expression of IgM+, CD19, CD20+, and CD79a+, and lack of expression of the CD5, CD10, CD23 antigens.² Molecular studies have identified MYD88^L2659 as the most common genetic abnormality in WM cells, followed by the CXCR4 mutation.³

The infiltration of WM cells can lower red blood cell, white blood cell, and platelet count, as well as causing dysfunctional iron metabolism, through a protein called hepcidin; these processes contribute towards the common clinical symptoms of anemia. WM treatments, such as Bruton’s tyrosine kinase inhibitors, work to reverse the function of WM cells and reduce anemia.²

Lymphoplasmacytic infiltration coupled with the destruction of healthy cells caused by WM treatment, leads to reduced production of polyclonal immunoglobulins; this results in a condition called hypogammaglobulinemia. Consequently, there is an increased risk of infection and intravenous immunoglobulins are administered to some patients to replenish the lacking antibodies.²

Bing-Neel syndrome (BNS) is a rare neurological complication of WM, affecting about 1% of patients.³ It is characterized by the infiltration of lymphoplasmacytic cells within the cerebrospinal fluid or the brain. The increased presence of WM cells within the central nervous system can cause variable symptoms including motor deficits and sensory disturbances.² Typical treatments used for systemic WM such as ibrutinib and bendamustine plus rituximab have proven to be effective in patients with BNS.²

Complications related to monoclonal IgM

High levels of circulating monoclonal IgM can give rise to significant complications. The physically large nature of IgM can disrupt circulation and increase blood thickness whilst its ‘sticky’ nature causes it to deposit within tissues. Cross-reactions between IgM and other proteins can cause further complications.

Hyperviscosity syndrome is one of the more common conditions, evidenced in up to 35% of WM cases, whereby high levels of the large IgM protein, usually >4 g/dL, causes thickening of the blood and yields a variety of clinical manifestations.^1,2 Patients can present with skin ulcers due to hyperviscosity causing the lack of oxygen supply to watershed areas such as the ankles. A lack of oxygen to the brain and extremities for the same reason can result in neurological symptoms and Raynaud’s phenomena, respectively. Within the eye, hyperviscosity can cause ‘sausaging’ of the blood vessels, leading to visual problems.²

Plasmapheresis may be used to address hyperviscosity syndrome. This procedure is usually initiated when patients present with a level of IgM >4 g/dL, as well as the following symptoms associated with hyperviscosity: visual deterioration, neurological symptoms, and bleeding. The use of single agent rituximab is not recommended in these patients as it has been shown to worsen symptoms. Alternatively, rituximab should be used in combination with or after other therapies.²

A common IgM-related complication, occurring in up to 40% of cases, is that of peripheral neuropathy.¹ In this disease, IgM adheres to proteins that are within the nerve sheath, inducing an immune response that causes demyelination of the nerve fibers and exposing the nerves. Symptoms associated with nerve damage and imbalanced muscle activity can include the appearance of an abnormally shaped foot. The electrical activity of the muscles can be tested using an electromyography to measure the speed of conduction, with medications for neuropathic pain commonly used to control the associated symptoms.²

Cryoglobulinemia is an unusual complication of WM, whereby the IgM becomes increasingly sticky and coagulates with other immunoglobulins, thickening and forming clumps when body temperature is low. Regardless of the level of IgM, these cryoglobulins deposits in tissues can cause leukocytoclastic vasculitis.² Cold agglutinin disease (CAD), another temperature-dependent disorder observed in 10% of cases,¹ occurs when IgM agglutinates with other red blood cells to form clumps in cold temperatures. This triggers autoantibody activity of the IgM against the red blood cell complexes, resulting in hemolytic anemia.^2,3

Aside from treatment to reduce production of monoclonal IgM, other preventative measures for cryoglobulinemia and CAD involve patients striving to stay above the thermal amplitude of the disease, possibly by relocating to a warmer climate.²

Some patients can experience an uncommon bleeding disorder called acquired von Willebrand disease, which is directly related to the hyperproduction of monoclonal IgM. The formation of complexes between IgM and a protein called von Willebrand factor disrupts the blood clotting process. The absence of functional von Willebrand factor can result in symptoms such as frequent nose bleeds, easy bruising, and bleeding gums.²

Another rare complication of WM is systemic amyloidosis, in which fragments of IgM deposit as aggregates within tissues of multiple organs. If present in the tongue, amyloidogenic IgM can manifest as an enlarged tongue, known as macroglossia, whereas deposits around the eyes can result in bruising. Diagnosis involves a bone marrow or abdominal fat aspirate to detect the presence of the amyloidogenic protein. Additionally, secondary to non-amyloid IgM deposits in the skin, Schnitzler’s syndrome can present with a textured-like skin rash.²

Conclusion

In conclusion, the infiltration of lymphoplasmacytic cells and nature of the IgM protein are responsible for various clinical manifestations of WM. Commonly associated symptoms include anemia, with rarer including hypogammaglobulinemia and BNS. For IgM-mediated conditions, hyperviscosity syndrome and peripheral neuropathy are more frequently seen, with a rarer incidence for cryoglobulinemia, CAD, acquired von Willebrand syndrome, systemic amyloidosis, and Schnitzler’s syndrome.

Management strategies for WM complications should focus on treating the underlying disease by targeting WM cells and reducing IgM production, standard treatments such as chemoimmunotherapy, Bruton’s tyrosine kinase inhibitors, and proteasome inhibitors are often used. The next step in management should involve effective measures to control the associated symptoms, such as cold avoidance in CAD and cryoglobulinemia or treating nerve pains related neuropathy. Some conditions will require specific procedures; thus, an accurate diagnosis of complications is crucial for targeted therapy options.